tag:blogger.com,1999:blog-22880883027996330142024-03-19T04:48:31.231-04:00The Unit: A Cardiology BlogPerspectives on cardiology practice, health care, and the profession of pharmacy.Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.comBlogger61125tag:blogger.com,1999:blog-2288088302799633014.post-89186640353922068362014-06-22T20:24:00.001-04:002017-05-28T16:32:08.286-04:00The Unit has moved!Update your bookmarks to <a href="http://www.reedrx.com/">http://www.reedrx.com/</a>.Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com9tag:blogger.com,1999:blog-2288088302799633014.post-34941655587863844512014-01-11T12:05:00.000-05:002014-01-11T17:13:36.374-05:00Digoxin, digoxout: an appraisal of digoxin immune fab<i>Preface: The inspiration for this topic came from an exchange on
Twitter between <a href="https://twitter.com/PharmERToxGuy" target="_blank">@PharmERToxGuy</a>, <a href="https://twitter.com/DavidJuurlink" target="_blank">@DavidJuurlink</a>, and I, representing one of
the things I love most about <a href="http://healthsocmed.com/" target="_blank">#hcsm</a> -- the opportunity for dialogue
across diverse backgrounds and practice settings. In this particular
case, we debated the appropriate use of digoxin immune fab (DigiFab</i><i><sup>®</sup>), which was certainly challenging to do in segments of 140 characters or less.
Below I have outlined a more detailed rationale for why I advocate its conservative use in the management of digoxin toxicity.</i><br />
<br />
My
reasons for advocating the conservative use of digoxin immune fab
(DigiFab<sup>®</sup>) are unrelated to its efficacy, as it is
undoubtedly
the most effective antidote for digoxin toxicity. Instead, I
contend that in many cases, it is an unnecessary and overly aggressive
-- if not a costly -- approach to a scenario that may be just
as effectively managed by thoughtful monitoring and supportive therapy.
While it can be challenging to predict whether patients might require
fab therapy at a later time, I believe a more judicious approach can be
made possible by considering the severity of toxicity, the circumstances in which it occurred, and whether fab administration would substantially alter the
clinical course of the patient.<br />
<br />
Digoxin toxicity is
difficult to characterize as a result of heterogeneity in the literature
(e.g., study methods, definitions for toxicity) and how use of digoxin
has evolved over time (i.e., patient populations, indications, dosing,
target concentrations). As an example, a patient with a ventricular
arrhythmia and serum digoxin concentration of 10.0 ng/mL in 1994 and one
with symptomatic bradycardia and a serum digoxin concentration of 2.0
ng/mL in 2014 are both classified as having digoxin toxicity (and both cases
often characterized simply as a <i>dysrhythmia</i>), although the severity of
their presentations is vastly different. These and similar challenges
may explain in part some of the discrepancies in the literature, as some
studies demonstrate a decline in the prevalence of digoxin toxicity
while others claim it has not changed [1-3].<br />
<br />
What
has changed considerably over the last several decades is how digoxin is
used. In the late 1980s and early 1990s, it was not uncommon for the
vast majority of patients with heart failure to be receiving digoxin
therapy -- as many as 9 out of 10 in some studies [4]. Today
those numbers are substantially fewer, as digoxin therapy is often reserved for
those patients with advanced symptomatic disease. When it is used in
this population, a lower serum concentration (i.e., 0.5 - 0.9 ng/mL) is targeted, ameliorating many of the more severe adverse effects
observed in the setting of elevated concentrations in the past [5,6]. Additionally, patients with heart failure are likely to be on concomitant therapies (e.g., beta blockers, aldosterone antagonists, implantable defibrillators and other devices) that may confer protection from some of the more severe forms of digoxin toxicity or prevent it altogether (e.g., less hypokalemia as a result of aldosterone antagonist use). Similar trends, including a decline in overall digoxin use and reservation for only the most advanced cases, have also been observed in the atrial fibrillation population, where lenient rate control targets have obviated the need for digoxin in many patients [7-9].<br />
<br />
Whether
or not these differences impact the number of patients
presenting with digoxin toxicity, they likely influence how, and perhaps
more importantly, why patients present. In my practice setting, digoxin
toxicity often manifests as a result of something more problematic
(i.e., renal impairment as a result of worsening heart failure,
emergence of underlying conduction abnormalities) rather than the consequence of a
drug-drug interaction or acute overdose. In these latter cases, fab
administration may be a reasonable approach for preventing hospital
admission. However, for the 4 out of every 5 patients with digoxin
toxicity who require hospitalization either way, fab administration may
not confer substantial benefit over what would be provided by monitoring
and symptomatic support [3]. <br />
<br />
Patients with
worsening heart failure often require days of clinical evaluation
whether or not they have signs or symptoms consistent with digoxin
toxicity (which can often mimic those of worsening heart failure).
Furthermore, complete digoxin withdrawal may actually worsen outcomes in
this population [6, 10]. In the case of renal impairment,
digoxin immune fab may not be an ideal strategy if renal impairment is advanced or does
not improve substantially, as it too requires renal clearance and is not
removed by hemodialysis. Although an earlier review substantiates fab use in patients with mild to moderate renal impairment, several limitations make it difficult to derive similar conclusions when renal impairment is severe [11]. Although manifestations of digoxin toxicity may initially improve in this latter population, recrudescent toxicity may occur days to weeks later as digoxin redistributes from peripheral tissues, a
phenomenon that has been well-documented in the literature [12, 13]. For patients on chronic digoxin therapy, this may occur even in the absence of severe renal impairment. In these scenarios, fab use may provide clinicians with a false sense of security, resulting in less frequent monitoring or premature discharge when the patient should be observed for recrudescent toxicity or worsening signs and symptoms of heart failure.<br />
<br />
Finally,
as I alluded to in several instances above, digoxin immune fab may not
be the most cost-effective strategy in a given patient. Notably, many
cost-effectiveness analyses are a decade or more older, making
them subject to the same limitations as the epidemiological studies described above. Given the
financial woes of today's health care environment,
cost-effectiveness should be a factor in determining whether a therapy
is indicated, especially when less expensive alternatives exist or if
the therapy is unlikely to alter the long-term outcome of the patient.
Otherwise, we endanger our ability to use these more expensive therapies in patients who
have no alternatives. In the US, a single vial of digoxin immune fab
costs between $1200-1500 (or more), and most patients require
multiple vials based on their body weight and/or serum digoxin
concentration. Unless hospitalization can be substantially shortened or
avoided altogether, the cost of fab therapy may quickly outpace reimbursement. For example, the average reimbursement for a
drug overdose at my institution runs about $6500, whereas a heart
failure admission runs around $8300 [14].<br />
<br />
That being said, the following are situations where I would definitely recommend the use of digoxin immune fab:<br />
<ul>
<li>Ventricular arrhythmias, accelerated junctional rhythms</li>
<li>Life-threatening bradyarrhythmias unresponsive to chronotropic agents (and when temporary pacing is not readily available)</li>
<li>Acute mental status changes</li>
<li>Acute overdose </li>
</ul>
I generally avoid recommending fab on the basis of a specific
serum digoxin concentration alone, as these are often open to interpretation
(e.g., timing of ingestion, laboratory draw). Furthermore, a <i>toxic</i>
concentration is any concentration that results in clinically meaningful adverse sequelae in a
given patient. A serum digoxin concentration of 2.0 ng/mL resulting in a
ventricular arrhythmia is toxic and requires emergent treatment,
while a patient with a serum concentration of 4.0 ng/mL and no adverse
sequelae requires close observation but emergent therapy is
not warranted.<br />
<br />
Outside the indications outlined above, the strategy I most commonly recommend
for managing digoxin toxicity is to simply facilitate urine output
(e.g., intravenous fluids), provide supportive therapy when
necessary, and monitor closely should a need for fab arise. If the patient has symptomatic bradycardia, this may require
intermittent use of a chronotropic agent. Although atropine is often
recommended in this scenario, its half life makes it less than ideal for counteracting a drug that may
require hours to days to clear. Instead, I prefer the use of a dopamine
infusion in this setting, as it may be turned on or off (or titrated) based on patient
need. Importantly, dopamine and other catecholamine-based therapies should be monitored closely so as not to exacerbate other rhythm disturbances commonly associated with digoxin toxicity.<br />
<br />
<i>Peer review: Special thanks goes to <a href="https://pharmacy.unc.edu/Directory/jerodger" target="_blank">Jo Ellen Rodgers, PharmD, FCCP, BCPS (AQ Cardiology)</a>, a clinical associate professor at the <a href="https://pharmacy.unc.edu/" target="_blank">University of North Carolina Eshelman School of Pharmacy</a>, and <a href="http://www.unchealthcare.org/site/pharmacy_residency/preceptors/medicine" target="_blank">Jonathan Cicci, PharmD, BCPS</a>, a clinical pharmacy specialist in cardiology at the <a href="http://www.unchealthcare.org/" target="_blank">University of North Carolina Health Care</a> for their review of this entry.</i><br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/18091761" target="_blank">Haynes K, Heitjan D, Kanetsky P, Hennessy S. Declining public health burden of digoxin toxicity from 1991 to 2004. Clin Pharmacol Ther. 2008 Jul;84(1):90–4.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/22444097" target="_blank">Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med. 2012 Apr;125(4):337–43. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/24300242" target="_blank">See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS. Emergency Department Visits and Hospitalizations for Digoxin Toxicity: United States, 2005-2010. Circ Heart Fail. 2013 Dec 3; </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/2883575" target="_blank">Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987 Jun 4;316(23):1429–35. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/12588271" target="_blank">Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA J Am Med Assoc. 2003 Feb 19;289(7):871–8. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17631083" target="_blank">Ahmed A, Gambassi G, Weaver MT, Young JB, Wehrmacher WH, Rich MW. Effects of discontinuation of digoxin versus continuation at low serum digoxin concentrations in chronic heart failure. Am J Cardiol. 2007 Jul 15;100(2):280–4. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/12466506" target="_blank">Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347(23):1825–33. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/19213680" target="_blank">Hohnloser SH, Crijns HJGM, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009 Feb 12;360(7):668–78. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/20231232" target="_blank">Van Gelder IC, Groenveld HF, Crijns HJGM, Tuininga YS, Tijssen JGP, Alings AM, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363–73. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/8505940" target="_blank">Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993 Jul 1;329(1):1–7. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/1997017" target="_blank">Wenger
TL. Experience with digoxin immune Fab (ovine) in patients with renal
impairment. Am J Emerg Med. 1991 Mar;9(2 Suppl 1):21–23; discussion
33–34. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/22618329" target="_blank">Rajpal S, Beedupalli J, Reddy P. Recrudescent digoxin toxicity treated with plasma exchange: a case report and review of literature. Cardiovasc Toxicol. 2012 Dec;12(4):363–8. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/24023070" target="_blank">Hazara AM. Recurrence of digoxin toxicity following treatment with digoxin immune fab in a patient with renal impairment. QJM Mon J Assoc Physicians. 2013 Sep 27; </a></li>
<li><a href="http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/index.html" target="_blank">Medicare C for, Baltimore MS 7500 SB, Usa M. Medicare Provider Charge Data Overview [Internet]. 2013 [cited 2013 Dec 24]. Available from: http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/index.html</a></li>
</ol>
<br />Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com7tag:blogger.com,1999:blog-2288088302799633014.post-17670935520351875672013-12-29T21:23:00.001-05:002013-12-29T21:23:23.223-05:00The year in review: top posts from 2013With the year quickly wrapping up, here is a look back at the top three posts from 2013:<br />
<ol>
<li><a href="http://reedb.blogspot.com/2013/05/cocaine-and-beta-blockers-all-its.html" target="_blank">Cocaine and beta blockers: all it's cracked up to be?</a><br />The proposed pharmacologic interaction between cocaine and beta blockers is one of the most oft-quoted, if not controversial, teaching points in all of cardiovascular medicine... but is there evidence to support it?<br /><i>Posted May 5, 2013</i><br /><br /></li>
<li><a href="http://reedb.blogspot.com/2013/08/the-trouble-with-diltiazem-infusions.html" target="_blank">The trouble with diltiazem infusions</a><br />Few therapies are more problematic in the cardiac intensive care unit than diltiazem infusions. Although effective for heart rate control, extended infusions are notorious for their adverse effects, including refractory bradycardia and hypotension.<br /><i>Posted August 11, 2013</i><br /><br /></li>
<li><a href="http://reedb.blogspot.com/2013/12/no-love-lost-for-labetalol-infusions.html" target="_blank">No love lost for labetalol infusions: risks of prolonged use</a> <br />Two cases where patients experienced life-threatening events prompted this review of continuous infusion labetalol and the dangers associated with prolonged use.<br /><i>Posted December 26, 2013</i></li>
</ol>
<br />
Apparently it was a good (or bad?) year for AV nodal blockers.Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-90233478509630084862013-12-26T08:22:00.001-05:002018-01-13T14:08:04.896-05:00No love lost for labetalol infusions: risks of prolonged useThis entry has been <a href="http://blogs.pharmacy.umaryland.edu/atrium/2017/10/07/no-love-lost-for-intravenous-labetalol-infusions-risks-of-prolonged-use/">moved</a>.Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com2tag:blogger.com,1999:blog-2288088302799633014.post-81268754814883541882013-12-07T14:56:00.000-05:002013-12-07T14:56:37.097-05:00ENGAGE-AF: Me too! Or four, rather… edoxaban represents yet another alternative to warfarin in patients with atrial fibrillation This entry is the fourth part of a series on late-breaking clinical trials from the American Heart Association Scientific Sessions 2013. For a list of all reviewed trials, click <a href="http://reedb.blogspot.com/2013/11/clinical-trial-highlights-from-american_24.html">here</a>. <br />
<br />
<i>Summary: </i><br />
In the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE-AF) trial [1], patients with atrial fibrillation and a CHADS<sub>2</sub> score of <u>></u> 2 were randomized in a double-blind, double-dummy fashion to either high-dose edoxaban (60 mg daily), low-dose edoxaban (30 mg daily), or warfarin titrated to an INR of 2-3. Patients with an estimated creatinine clearance (CrCl) < 30 mL/min and those taking dual antiplatelet therapy were excluded. The dose of edoxaban was halved if patients were <u><</u> 60 kg, had a CrCl of 30-50 mL/min, or if a strong p-glycoprotein inhibitor (i.e., dronedarone, quinidine, verapamil) was added. Notable baseline characteristics include median age of 72, history of stroke in 28.3% and heart failure in 57.4%; over three-fourths of patients had a CHADS<sub>2</sub> score < 3. The median time in therapeutic range (TTR) for those on warfarin was 68.4%. <br />
<br />
In terms of the primary endpoint of stroke or systemic embolism, both doses of edoxaban were non-inferior to warfarin (1.18% with high-dose edoxaban and 1.61% with low-dose edoxaban vs. 1.50% with warfarin [p < 0.001 and p = 0.005, respectively]). While a trend favoring edoxaban was observed in the superiority analysis, it did not reach statistical significance. Rates of major bleeding were lower with both doses of edoxaban (2.75% and 1.61% with high and low-dose edoxaban vs. 3.34% with warfarin, both p < 0.001), as were rates of intracranial hemorrhage. Gastrointestinal bleeding (GI) was higher with edoxaban. Improvements in several key secondary endpoints were also observed with edoxaban, including death from cardiovascular causes. Patients receiving the lower dose of edoxaban had a higher rate of ischemic strokes, while rates were similar among those on warfarin and high-dose edoxaban. <br />
<br />
<i>Commentary: </i><br />
With a few exceptions, the findings of ENGAGE-AF are almost identical to those observed in the comparison of rivaroxaban, another factor Xa inhibitor, and warfarin in the ROCKET-AF trial [2]. Most experts argue that is not possible to compare the new oral anticoagulants with each other because none were studied head-to-head. While this is true from the standpoint of academic purity, it does little to guide the clinician when faced with the challenge of selecting an agent in an individual patient. For this latter case, a discussion of the similarities and differences are important. <br />
<br />
Similarities between ENGAGE-AF and ROCKET-AF include:<br />
<ul>
<li>Trial design: both were randomized, double-blind, double-dummy trials</li>
<li>Inclusions/exclusions: similar thresholds for renal function, high-risk exclusions (e.g., patients on concomitant dual antiplatelet therapy were excluded) </li>
<li>Drug dosing: once daily dosing vs. warfarin titrated to an INR of 2-3 </li>
<li>Efficacy: both shown to be non-inferior to warfarin </li>
<li>Safety: both safer than warfarin in the severest of safety endpoints (fatal bleeding, intracranial hemorrhage), but higher rates of GI bleeding </li>
</ul>
<br />
A few key differences:<br />
<ul>
<li>Study population: on average, the patients enrolled in ENGAGE-AF were healthier than those in ROCKET-AF, as demonstrated by lower median CHADS<sub>2</sub> scores and fewer patients with a history of stroke or heart failure</li>
<li>Warfarin management: warfarin was more optimally managed in ENGAGE-AF based on a TTR of 68.4% compared to 55% in ROCKET-AF; that being said, INR control is closely related to overall health status, so the fact that the INR was less problematic in the healthier population of ENGAGE-AF is not altogether surprising </li>
<li>Safety endpoints: although both drugs reduced the incidence of severe bleeding, rivaroxaban was similar to warfarin in the primary safety endpoint of major bleeding, whereas edoxaban was safer in ENGAGE-AF </li>
<li>Transition at study termination: the investigators of ENGAGE-AF should be applauded for the lessons learned from ROCKET-AF, where rebound thrombotic events were observed among patients being transitioned from rivaroxaban to open-label warfarin at conclusion of the trial. At the end of ENGAGE-AF, a carefully monitored transition from edoxaban to warfarin was performed, resulting in no differences in rebound thrombotic events </li>
<li>Differences in secondary endpoints: edoxaban showed improvements in some secondary endpoints (e.g., cardiovascular death, other composites) </li>
</ul>
<br />
So now that edoxaban will represent the fourth alternative to warfarin, what are clinicians to do? To be honest, it is my personal opinion that edoxaban offers few if any clinical advantages to rivaroxaban. Despite being studied in a healthier population (i.e., where differences in drug metabolism and clearance are less likely to complicate management), edoxaban was still only non-inferior to warfarin. While it was safer than warfarin in terms of major bleeding, this could again be attributed to the healthier nature of the patient population. Both rivaroxaban and edoxaban reduced the incidence of the severest safety endpoints – fatal bleeding and intracranial hemorrhage. <br />
<br />
Compared to the other new oral anticoagulants apixaban and dabigatran, my feelings on edoxaban are similar to rivaroxaban, which I wrote about in <a href="http://reedb.blogspot.com/2011/11/rivaroxaban-approved-for-stroke.html" target="_blank">this entry in November 2011</a> and <a href="http://reedb.blogspot.com/2012/10/selecting-oral-anticoagulant-in.html" target="_blank">again in October 2012</a>. I still tend to favor apixaban as my first-line alternative to warfarin based on it having the most comparative advantages, although I would still consider dabigatran in younger patients with normal renal function. The whole notion that the once daily dosing made possible by rivaroxaban, and now edoxaban, is more ideal for less compliant patients is still a dangerous proposition (see my note at the end of the <a href="http://reedb.blogspot.com/2012/10/selecting-oral-anticoagulant-in.html" target="_blank">selection tool posted in October 2012</a>). For patients likely to miss doses, a once daily drug that only lasts half a day actually offers less protection from stroke and systemic embolism than one taken twice daily. <br />
<br />
<i>Bottom line</i>: <br />
Edoxaban is non-inferior to warfarin for preventing stroke and systemic embolism in patients with atrial fibrillation while reducing the risk of major bleeding. <br />
<br />
<b>References </b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/24251359" target="_blank">Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093–104.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/21830957" target="_blank">Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883–91. </a></li>
</ol>
<br />Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com3tag:blogger.com,1999:blog-2288088302799633014.post-18898805847110648302013-11-30T12:59:00.000-05:002013-11-30T12:59:25.992-05:00COAG, EU-PACT, and a tale of three trials: pharmacogenomic-guided warfarin dosingThis entry is the third part of a series on late-breaking clinical trials from the American Heart Association Scientific Sessions 2013. For a list of all reviewed trials, click <a href="http://reedb.blogspot.com/2013/11/clinical-trial-highlights-from-american_24.html">here</a>.<br />
<br />
<i>Summaries:</i><br />
COAG: In the Clarification of Optimal Anticoagulation through Genetics (COAG) study [1], 1015 patients at sites throughout the US were randomized to an initial warfarin dosing strategy that incorporated both pharmacogenomic and clinical factors or clinical factors only. After 5 days, both arms were managed according to a standardized adjustment algorithm. At 4 weeks of follow-up, there was no difference in the primary outcome of INR time-in-therapeutic range (TTR) between the two groups (45.2% vs. 45.5% in the pharmacogenomic and clinically-guided group, respectively, p = 0.91). A difference was found only in the subgroup of self-identified black patients, where TTR was lower with the pharmacogenomic-guided strategy (35.2% vs. 43.5% with control, p = 0.01). No differences in thrombotic or bleeding events were observed.<br />
<br />
EU-PACT trials: In a similarly designed study conducted by the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) group [2], 548 patients were randomized to a warfarin dosing strategy that used both pharmacogenomic and clinical factors or clinical factors only. After the first 5-7 days, patients were managed according to local standards of practice. At a follow-up of at least 10 weeks, no difference in the primary endpoint of TTR was observed between the two groups (61.6% vs. 60.2% in the pharmacogenomic and clinically-guided groups, respectively, p = 0.52). An improvement in TTR was observed with pharmacogenomic-guided dosing at 4 weeks (52.8% vs. 47.5% with control, p = 0.02), a pre-specified secondary endpoint of the study. No differences were observed in specific subgroups, nor were there any differences in clinical outcomes.<br />
<br />
In a second trial conducted by the EU-PACT group [3], 455 patients were randomized to a dosing strategy comprised of both pharmacogenomic and clinical factors or usual care, which was defined as an initial dosing strategy of 10 mg, 5 mg, and 5 mg for days 1-3 among patients <u><</u> 75 years of age and 5 mg daily for days 1-3 in patients > 75 years. After 5 days, patients were managed according to local standards of care. After a follow-up period of 12 weeks, the pharmacogenomic-guided strategy improved TTR by a mean 7% (67.4% vs. 60.3% with usual care, 95% CI 3.3-10.6, p < 0.001). The median time to reach therapeutic INR was 8 days shorter in the pharmacogenomic-guided group (21 days vs. 29 days with usual care, p < 0.001). No differences in clinical endpoints were observed.<br />
<br />
<i>Commentary:</i><br />
Let me be first to admit that I missed the fact that there were <i>three</i> studies of pharmacogenomic-guided warfarin dosing strategies published simultaneously. The major headline from AHA13 was that this strategy did not confer significant improvements in the management of therapy, and I walked away thinking that was the end of the story. I even <a href="https://twitter.com/brentnreed/status/402843991298674688" target="_blank">tweeted</a> so. However, based on the findings of the third study, I think further discussion of these trials is warranted.<br />
<br />
<i>Note: For the sake of simplicity, I will refer to the EU-PACT study that compared pharmacogenomic plus clinical factors versus clinical factors alone as EU-PACT-1 and the study comparing pharmacogenomic plus clinical factors to usual care as EU-PACT-2.</i><br />
<br />
First, the COAG and EU-PACT-1 trials were almost identical in design, with the main difference being their length of follow-up (4 weeks in COAG vs. a minimum of 10 weeks and goal of 12 weeks in EU-PACT-1) [1,2]. Both obtained genotypes for the major polymorphisms expected to influence warfarin management (i.e., CYP2C9 an VKORC1) and compared 5 days of an algorithm that combined this information with clinical features already known to impact warfarin dosing (intervention) versus an algorithm that used only clinical features (control). While this design was essential for determining whether the addition of genetic information would influence outcomes, one should be cautious not to interpret the control arm as representing the standard of care for most practices. As an example of how complex the control algorithm was, the following equation was used to determine the initial dose of warfarin in COAG:<br />
<br />
<blockquote class="tr_bq">
Dose (in mg/day) = exp[0.613 – (0.0075 x age) + (0.156 if black race) + (0.108 if smokes) + (0.425 x body surface area) – (0.257 if on amiodarone) + (0.216 x target INR) + (0.0784 if indication for warfarin is DVT/PE)]</blockquote>
<br />
While these and other dosing calculations have been validated in smaller studies, I am not aware of any large robust clinical trials comparing them to usual care. Even so, they are not included in current practice guidelines and are therefore unlikely to be widely used. Whether or not they have been validated, they certainly incorporate many of the features one should consider when managing warfarin therapy. Given their inclusion in the dose determinations for these two studies, I am not surprised that the addition of genetic characteristics failed to have an incremental impact on TTR control in a study of only a few hundred patients. I imagine many thousands of patients would be necessary to distinguish the impact of genetic characteristics on top of all of the other adjustments already included in the equation. <br />
<br />
Although no differences in TTR were observed at 4 weeks in COAG, an improvement with the pharmacogenomic-guided dosing strategy <i>was</i> observed at this time interval in EU-PACT-1 (although the primary analysis was conducted at 12 weeks). The cause of this discrepancy is unclear but the poor performance of the pharmacogenomic-guided algorithm among blacks in COAG (40% of the study population) may have been a contributor.<br />
<br />
The design of EU-PACT-2 represents a more accurate comparison of a pharmacogenomic-guided dosing strategy and usual care [3]. While some ambulatory care practices and inpatient consultation services may utilize equations similar to the ones highlighted above, the vast majority of patients receiving a diagnosis that warrants anticoagulation therapy are initiated on a fixed dose with subsequent adjustments for changes in INR. The specific dose selected often incorporates many of the features included in these dosing equations, but not in a formal sense. When compared to this usual care approach, EU-PACT-2 demonstrated that a strategy incorporating both pharmacogenomic and clinical factors improves TTR control. Unfortunately, because an arm comprised of patients being managed using only clinical factors was not included in this trial, it is impossible to know the true incremental impact of genetic information on warfarin dosing.<br />
<br />
Finally, all three trials were conducted mostly at large academic medical centers with access to specialist providers, including pharmacists specifically trained in the management of anticoagulation therapy. Although the intervention was largely blinded for the first 5-7 days, the specialized care provided at these centers may have influenced the potential impact of the pharmacogenomic-guided strategy by the end of study follow-up at 4-12 weeks. What would have been more interesting to know is whether this strategy would have conferred improvements among patients managed by general care practitioners or those discharged from the hospital who were unable to follow up for INR management until 1-2 weeks later. Perhaps my practice environment has biased me, but I feel these latter scenarios are far more common.<br />
<br />
<i>Bottom line:</i><br />
The addition of genetic information to an algorithm already incorporating clinical features known to influence warfarin dosing does not improve management at 12 weeks, although differences may be observed in certain subgroups or at earlier time points. On the other hand, an algorithm incorporating both genetic and clinical information significantly improves warfarin management when compared to usual care.<br />
<br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/24251361" target="_blank">Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, et al. A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing. N Engl J Med. 2013 Nov 19;</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/24251360" target="_blank">Verhoef TI, Ragia G, de Boer A, Barallon R, Kolovou G, Kolovou V, et al. A Randomized Trial of Genotype-Guided Dosing of Acenocoumarol and Phenprocoumon. N Engl J Med. 2013 Nov 19;</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/24251363" target="_blank">Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, et al. A Randomized Trial of Genotype-Guided Dosing of Warfarin. N Engl J Med. 2013 Nov 19; </a></li>
</ol>
<br />Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-54271329786794777932013-11-23T14:50:00.001-05:002013-11-30T12:38:35.465-05:00TOPCAT: not purrfect, but a signal of benefit with spironolactone in heart failure with preserved ejection fractionThis entry is the second part of a series on late-breaking clinical trials from the American Heart Association Scientific Sessions 2013. For a list of all reviewed trials, click <a href="http://reedb.blogspot.com/2013/11/clinical-trial-highlights-from-american_24.html">here</a>.<br />
<br />
<i>Note: details of this trial have not yet been published, so the following has been compiled from <a href="http://clinicaltrials.gov/show/NCT00094302">ClinicalTrials.gov</a> and results presented at AHA13.</i><br />
<br />
<i>Summary:</i><br />
In
the Treatment of Preserved Cardiac Function Heart Failure with an
Aldosterone Antagonist (TOPCAT) trial, 3445 patients with heart failure
with preserved ejection fraction (HFpEF) were randomized in a
double-blind fashion to spironolactone (15 mg titrated to 30-45 mg per
day) or placebo. Investigators defined HFpEF as the presence of at
least one sign and symptom of heart failure and EF <u>></u> 45%.
Patients were also required to have controlled systolic blood pressure
(SBP < 140 mmHg or < 160 mmHg if taking <u>></u> 3
antihypertensive medications) and serum potassium < 5.0 mEq/L.
The mean systolic blood pressure at enrollment was 129.2±14.0 mmHg and
potassium was 4.3±0.4 mEq/L. Other notable characteristics at baseline
included the presence of hypertension in 91% of patients and chronic
kidney disease in 39%. Additionally, 84% of patients were taking an ACE
inhibitor (ACEi) or angiotensin receptor blocker (ARB), and 82% were
taking a diuretic. <br />
<br />
After an average follow-up of 3.3
years, spironolactone failed to reduce the primary endpoint, a composite
of cardiovascular mortality, cardiac arrest, or heart failure
hospitalizations (18.6% vs. 20.4%, HR 0.89 (95% CI 0.77-1.04), p =
0.138). Spironolactone was more effective at reducing heart failure
hospitalizations alone (12.0% vs. 14.2% with placebo, HR 0.83 (95% CI
0.69-0.99), p = 0.042), but it also doubled the rate of hyperkalemia
(defined as serum potassium > 5.5 mEq/L) (18.7% vs. 9.1% with
placebo, p < 0.001) and increased the incidence of renal failure
(data not available at the time of writing). In a post-hoc analysis of
TOPCAT, regional variability was observed, as patients in the Eastern
Hemisphere (primarily Russia and the Republic of Georgia) did not
benefit from the addition of spironolactone while a slight benefit was
observed among patients in the Americas (HR 0.82 (95% CI 0.69-0.98)).<br />
<br />
<i>Commentary: </i><br />
The
results of TOPCAT follow a consistent theme in patients with HFpEF – no
therapies have been shown to have a substantial impact on disease
progression and it remains an incredibly difficult condition to treat.
Optimism for spironolactone had been high due in part to the results of
Aldo-DHF, where its use resulted in improvements in left ventricular
function, although no differences in clinical endpoints were observe
[1]. Authors attributed this lack of benefit to the short duration of
the study and its relatively young, healthy population. However, as
TOPCAT revealed, spironolactone does not appear to confer significant
benefit even when a larger and sicker population is followed for a
longer period of time.<br />
<br />
Several findings from TOPCAT are
worth further comment. Although the results were largely negative, the
fact that spironolactone reduced heart failure hospitalizations may be a
signal of benefit in carefully selected patients, such as those who can
be monitored closely for hyperkalemia and changes in renal function.
Although some experts have heralded it as the first study to show a
benefit in HFpEF, this is not entirely accurate, as candesartan
demonstrated similar improvements in heart failure hospitalizations as a
secondary endpoint of the CHARM-Preserved trial [2]. Nonetheless, it
does represent another potential approach in a patient population with
so few therapeutic options.<br />
<br />
Some of the baseline
characteristics of patients in TOPCAT also warrant further discussion.
The vast majority had hypertension, which is not altogether unsurprising
given its role in the pathophysiology of HFpEF. However, the fact that
patients were required to have controlled hypertension may have limited
the impact of spironolactone. I recognize this probably had to be done
to assess whether the potential impact of spironolactone was independent
of its effects on blood pressure. However, given the number of trials
showing benefit with spironolactone in refractory hypertension (as well
as the role of hypertension in HFpEF), perhaps spironolactone would have
been better than the medication therapies patients were required to be
on in order to meet inclusion criteria. For example, the incidence of
hyperkalemia (and the results this may have had on the primary endpoint)
may not have been so high had so many patients not been taking ACEi or
ARB therapy. <br />
<br />
The higher rate of renal failure
observed in the spironolactone arm is also intriguing, as a similar
result was observed in Aldo-DHF, but this finding is not consistent with
trials of aldosterone antagonists in patients with heart failure with
reduced ejection fraction (HFrEF). Many patients with HFpEF are
notoriously preload dependent, which can complicate strategies for
maintaining appropriate volume status. Spironolactone is a weak diuretic
at the low doses commonly used in HFrEF and usually has only minimal
impact on volume status in most patients, even when combined with loop
diuretics. However, could it have had a more substantial impact in
patients with HFpEF given the more tenuous nature of their volume
status? In TOPCAT, 4 out of every 5 patients were already on a diuretic
at baseline – could the addition of spironolactone have been enough to
tip the balance toward hypovolemia and subsequent renal failure? <br />
<br />
All
in all, I would still consider spironolactone in select patients with
HFpEF (i.e., those who can be monitored for changes in serum potassium
concentrations and renal function). I would especially consider its use
in patients with HFpEF and refractory hypertension as well as those for
whom only minor diuresis is necessary to maintain volume status. That
being said, I am definitely cautious about its use in combination with
diuretics or ACEi or ARB therapy. In fact, given the lack of benefit
shown with these other agents, I think it would be reasonable to
consider spironolactone <i>first</i> based on its potential for reducing
heart failure hospitalizations (and potential for adverse events when
combined with other agents).<br />
<br />
<i>Bottom line:</i><br />
Similar
to the agents studied before it, spironolactone does not substantially
impact clinical outcomes in patients with HFpEF. It appears to reduce
heart failure hospitalizations, but does so at the expense of increased
rates of hyperkalemia and renal failure. Accordingly, its use should
only be considered in select patients. <br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/23443441">Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA J Am Med Assoc. 2013 Feb 27;309(8):781–91. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/13678871">Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet. 2003 Sep;362(9386):777–81. </a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-42501080628043944822013-11-21T21:22:00.000-05:002013-11-30T12:39:24.729-05:00ROSE AHF: Mostly thorns for low-dose dopamine, nesiritide in acute decompensated heart failure and renal impairmentThis entry is the first part of a series on late-breaking clinical
trials from the American Heart Association Scientific Sessions 2013. For a list of all reviewed trials, click <a href="http://reedb.blogspot.com/2013/11/clinical-trial-highlights-from-american_24.html">here</a>.<br />
<br />
<i>Summary: </i><br />
In
the Renal Optimization Strategies Evaluation in Acute Heart Failure
(ROSE AHF) trial [1], patients with acute decompensated heart failure (ADHF)
and renal impairment were randomized in a double-blind fashion to 72
hours of low-dose dopamine (2 mcg/kg/min), low-dose nesiritide (0.005
mcg/kg/min), or placebo. Patients were eligible for enrollment if they
had at least one sign and symptom of ADHF (irrespective of ejection
fraction) and an estimated glomerular filtration rate (eGFR) of 15-60
mL/min/1.73 m<sup>2</sup>. Baseline characteristics were similar between
the three groups with a median systolic blood pressure of 115 mmHg,
median ejection fraction (EF) of 33% (over two-thirds with EF <
50%), and eGFR of 42 mL/min/1.73 m<sup>2</sup>. <br />
<br />
Low-dose
dopamine failed to produce a difference in the co-primary endpoints of
cumulative urine output (UOP) or change in cystatin C at 72 hours
compared to placebo (differences in UOP of 8254 mL and 8296 mL,
respectively, p = 0.59). Drug discontinuation was similar between the
two groups, although low-dose dopamine was more likely to be
discontinued for tachycardia (7.2% vs. 0.9% with placebo, p <
0.001) while placebo was discontinued more frequently for hypotension
(10.4% vs. 0.9% with low-dose dopamine, p < 0.001). Likewise,
low-dose nesiritide also failed to confer significant differences in the
co-primary endpoint (differences in UOP of 8574 mL and 8296 mL with
placebo, p < 0.49). Compared to placebo, hypotension was more
common in the low-dose nesiritide group (18.8% vs. 10.4% with placebo, p
= 0.07). Results for the co-primary endpoints were similar across
subgroups with the exception of EF. Compared to dopamine, patients with
preserved EF tended to do better with placebo (p = 0.01 for
interaction). In contrast, nesiritide appeared to benefit those with
reduced EF, although this difference was not statistically significant.
No differences in clinical endpoints (e.g., symptom relief, death,
rehospitalization) were observed between any of the groups.<br />
<br />
<i>Commentary: </i><br />
Those
who follow my blog know that I am no fan of using low-dose dopamine for
the purposes of renoprotection in ADHF (previous entries <a href="http://reedb.blogspot.com/2010/09/low-dose-dopamine-still-myth-part-1.html" target="_blank">here</a> and <a href="http://reedb.blogspot.com/2012/06/innovation-or-impersonation-low-dose.html" target="_blank">here</a>).
While I am not opposed to its use as a mixed inotrope/vasopressor
(i.e., for patients in whom peripheral vasodilation from a traditional
inotrope might compromise hemodynamics), the renoprotective properties
of low-dose dopamine have been widely discredited [2]. Given the lack of
benefit observed in ROSE AHF, hopefully this myth has been debunked
once and for all. Importantly, dopamine not only failed to produce a
significant difference in the co-primary endpoints; it also resulted in
lower rates of hypotension and higher rates of tachycardia, indicating
that even at doses as low as 2 mcg/kg/min, dopamine is not entirely
selective for renal vascular beds.<br />
<br />
Unfortunately, a
signal of differential response between those with reduced versus
preserved EF was observed (although not statistically significant),
which may provide just enough justification to continue evaluating this
approach in select subgroups. Although the inclusion of a low-dose
nesiritide arm in this study was an interesting hypothesis, the fact
that it did not produce a meaningful difference in outcomes is not
altogether unsurprising.<br />
<i><br /></i>
<i>Bottom line: </i><br />
Neither low-dose dopamine nor low-dose nesiritide provide renoprotective effects in patients with ADHF and renal impairment.<br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/24247300">Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, et al. Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction: The ROSE Acute Heart Failure Randomized Trial. JAMA J Am Med Assoc. 2013 Nov 18;</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/24214219">Cicci JD, Reed BN, McNeely EB, Oni-Orisan A, Patterson JH, Rodgers JE. Acute Decompensated Heart Failure: Evolving Literature and Implications for Future Practice. Pharmacotherapy. 2013 Nov 11;</a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-27186529020612396982013-11-20T10:09:00.000-05:002013-12-07T14:57:45.442-05:00Clinical Trial Highlights from the American Heart Association Scientific Sessions 2013 (AHA13)Over the next couple of weeks, I will be providing trial summaries
and commentary on all of the medication-related late-breakers from the
American Heart Association Scientific Sessions (AHA13). Although there
were few breakthroughs presented at the meeting, <a href="http://physiciandirectory.brighamandwomens.org/Details/1225">Marc Pfeffer</a>,
MD, PhD, professor at the Harvard Medical School and lead investigator
for the TOPCAT trial, cautioned attendees to refrain from calling the
results negative, as the true purpose of research is to learn even if
the results are not beneficial.<br />
<br />
Keep checking back for updates!<br />
<br />
Posted as of December 7, 2013:<br />
<ul>
<li><a href="http://reedb.blogspot.com/2013/12/engage-af-me-too-or-four-rather.html" target="_blank">ENGAGE-AF: edoxaban vs. warfarin in patients with atrial fibrillation </a></li>
<li><a href="http://reedb.blogspot.com/2013/11/coag-eu-pact-and-tale-of-three-trials.html">COAG, EU-PACT: pharmacogenomic-guided dosing strategies for warfarin </a></li>
<li><a href="http://reedb.blogspot.com/2013/11/topcat-not-purrfect-but-signal-of.html">TOPCAT: spironolactone vs. placebo in heart failure with preserved ejection fraction </a></li>
<li><a href="http://reedb.blogspot.com/2013/11/rose-ahf-mostly-thorns-for-low-dose.html">ROSE AHF: low-dose dopamine of low-dose nesiritide in acute decompensated heart failure</a></li>
</ul>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com0tag:blogger.com,1999:blog-2288088302799633014.post-7269049581505254152013-09-22T15:13:00.000-04:002013-09-22T15:21:49.498-04:00Should tolvaptan be used routinely for hyponatremia in patients with heart failure? Na.One can hardly open a medical publication without seeing an advertisement for Otsuka's tolvaptan (Samsca<sup>®</sup>), an oral vasopressin antagonist approved for the management of hyponatremia in the setting of heart failure. Despite only minimal improvements in clinical trials and new warnings issued by the US Food & Drug Administration (FDA), the use of tolvaptan remains a topic of interest.<br />
<br />
Hyponatremia is common among hospitalized patients and is associated with poor prognosis among those with heart failure [1]. What is less clear, however, is whether this relationship is a result of cause-and-effect or merely correlation. The latter is worth investigating, as this has been observed with other surrogate markers that were once considered potential therapeutic targets, with hemoglobin being one of the most recent to be called into question [2].<br />
<br />
To date, the available evidence suggests that, while serum sodium concentrations can be improved with vasopressin antagonist therapy, these changes do not appear to confer meaningful differences in clinical outcomes. In SALT, a trial evaluating the use of tolvaptan in patients with hyponatremia (a third of whom had heart failure), patients randomized to tolvaptan experienced improvements in urine output and serum sodium concentrations, but this only persisted while patients were on therapy; in less than a week after discontinuing tolvaptan, serum sodium concentrations returned to baseline [3]. In EVEREST, a trial specifically enrolling patients with acute decompensated heart failure (irrespective of serum sodium concentrations), those randomized to tolvaptan experienced greater reductions in body weight (although less than a kg difference versus placebo) and improvements in some but not all heart failure signs and symptoms [4]. Tolvaptan failed to impart any clinically meaningful differences in mortality, hospitalizations, worsening heart failure, or quality of life [5]. Serum sodium concentrations improved initially but these differences dissipated with time. <br />
<br />
In other words, tolvaptan and other vasopressin antagonists appear to have no appreciable effect on the underlying pathophysiology of heart failure. While serum sodium concentrations can be improved, recurrence of hyponatremia should be expected following cessation of therapy if underlying causes (e.g., reduced renal perfusion, hypervolemia, etc.) are not addressed. Coupled with emerging evidence of liver injury that eventually <a href="http://www.fda.gov/Drugs/DrugSafety/ucm350062.htm" target="_blank">prompted FDA</a> to limit its use to less than 30 days (and avoid it altogether in patients with evidence of liver impairment), tolvaptan has only limited utility in patients with heart failure.<br />
<br />
There are a couple of scenarios where a short course of tolvaptan may be considered:<br />
<ul>
<li>Patients with symptomatic hyponatremia at any serum sodium concentration; or,</li>
<li>As a temporizing measure (i.e., up to 5 days or so) to stabilize critically low serum sodium concentrations (< 125 mEq/L, to prevent patients from becoming symptomatic) while underlying causes are corrected, i.e., discontinuation of potentially offending drugs (select antipsychotics and antidepressants, thiazide diuretics), optimization of standard heart failure therapies, addition of vasodilators or inotropes to improve renal perfusion, or aggressive diuresis to correct hypervolemia.</li>
</ul>
That being said, there is evidence that suggests small boluses of hypertonic saline can improve hyponatremia in these scenarios without worsening fluid balance [6].<br />
<br />
In summary, routine use of tolvaptan should be avoided, as it both fails to improve long-term clinical outcomes and represents an incredibly expensive strategy for improving symptoms and/or treating a surrogate marker that has yet to be associated with improved clinical endpoints. Although the price of tolvaptan has likely come down since its introduction to the market, at one time its use represented spending about $50 for each mEq/L increase in serum sodium concentration per day, and about $3 for each additional mL of urine output per day.<br />
<br />
<i>Note: I borrowed the title for this entry from an old <a href="http://chemistry.about.com/od/chemistryjokes/ig/Chemistry-Cat/Chemistry-Cat---Sodium-Jokes.htm" target="_blank">Chemistry Cat</a> meme, so let me end by giving credit (or blame?) to whomever it is due.</i><br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/15846257" target="_blank">Adams KF Jr, Fonarow GC, Horton DP, et al; ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005 Feb;149(2):209-16.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/23473338" target="_blank">Swedberg K, Young JB, van Veldhuisen DJ, et al; for the RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013 Mar 28;368(13):1210-9.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17105757" target="_blank">Schrier RW, Gross P, Orlandi C, et al; for the SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17384438" target="_blank">Gheorghiade M, Konstam MA, Orlandi C, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007 Mar 28;297(12):1332-43.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17384437" target="_blank">Konstam MA, Gheorghiade M, Orlandi C, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 28;297(12):1319-31.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/12660669" target="_blank">Licata G, Di Pasquale P, Paterna S, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: long-term effects. Am Heart J. 2003 Mar;145(3):459-66.</a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com0tag:blogger.com,1999:blog-2288088302799633014.post-83537451726873439782013-08-17T16:38:00.000-04:002013-08-17T16:49:28.890-04:00Perspectives on the Bush stenting case: lifestyle modifications and the risk of cardiovascular diseaseSignificant controversy (examples <a href="http://well.blogs.nytimes.com/2013/08/15/heart-stents-continue-to-be-overused/?_r=0" target="_blank">here</a>, <a href="http://www.bloomberg.com/news/2013-08-06/former-president-s-stent-surgery-reopens-debate-on-heart-care.html" target="_blank">here</a>, and <a href="http://www.boston.com/lifestyle/health/blogs/daily-dose/2013/08/12/was-george-bush-stent-surgery-really-unnecessary/DzklhNCGVlgriNxgpKZtuO/blog.html" target="_blank">here</a>) has surrounded whether former President George W. Bush should have undergone percutaneous coronary intervention (PCI) and stent placement. Many have called PCI an overly aggressive strategy based on his clinical presentation, citing studies that have shown no advantages with PCI among patients with stable coronary artery disease (CAD) [1]. However, the purpose of this entry is not to discuss the clinical appropriateness of the stent (as few individuals outside of the team taking care of Bush have the data to determine this), but instead how his case has refocused attention on the pathophysiology of CAD (for an elegant explanation of this, see <a href="http://www.drjohnm.org/2013/08/the-george-w-bush-stent-case-an-incredible-teaching-opportunity-on-the-basics-of-heart-disease/" target="_blank">John M's blog</a>) and more importantly, how living a healthy lifestyle is not always the be-all end-all strategy for reducing one's cardiovascular risk.<br />
<br />
First, let me be clear that the association between cardiovascular disease and many of the characteristic features of an unhealthy lifestyle (e.g., poor nutrition, excess sodium intake, physical inactivity) is undeniable. In fact, the growing prevalence of these traits is largely responsible for the rate at which cardiovascular disease has overtaken malnutrition and infectious diseases as the most common cause of worldwide morbidity and mortality. <br />
<br />
Unfortunately, these associations have also been used to stigmatize many patients with cardiovascular disease as simply paying the dues for a lifetime of poor decisions, and how easily their problems could be "fixed" with healthier choices (or by that same token, why health care benefits should not be provided to them for their past indiscretions). Often these statements come from individuals who can ably afford a gym membership (or live in a neighborhood where it is safe enough to exercise outside), can purchase fresh foods (not to mention having the time to properly prepare them), or who were raised in homes or school systems where they were taught the importance of nutrition and exercise. In Bush's case, we have an individual who purportedly eats healthy, exercises regularly (he recently completed a 100-km bike ride), and has access to the best preventative care in the world, yet has CAD significant enough to at least warrant discussion of coronary stent placement.<br />
<br />
While making healthy lifestyle decisions can undoubtedly reduce one's risk of cardiovascular disease, the risk never evaporates entirely. More importantly, the impact of these decisions on cardiovascular risk is a complex interplay of genetic, physiologic, and biochemical interactions, many of which we do not understand or have any influence upon. Even if we did reach consensus on what exaxctly constitutes a healthy lifestyle (for example, what should the <a href="http://www.theheart.org/article/1540363.do" target="_blank">daily limit of sodium</a> be?), it is not clear that everyone would respond favorably, if at all. A recent example of this was observed in the Look AHEAD trial, where aggressive changes in diet and increased physical activity failed to improve outcomes among overweight patients with diabetes [2].<br />
<br />
A predisposition to developing cardiovascular disease has already been well-characterized among several congenital disease states and conditions, such as type 1 diabetes, familial hypercholesterolemia, and a number of kidney disorders. Even cardiovascular risk factors traditionally characterized as being under the influence of lifestyle decisions (e.g., hypertension, type 2 diabetes) can be impacted significantly by underlying genetic differences. For example, African Americans are known to demonstrate enhanced sodium retention as well as low plasma renin activity, making them more susceptible to hypertension and conferring differences in how they respond to certain classes of antihypertensive medications [3]. Similar effects have also been observed with diabetes, where both African Americans and American Indians have been shown to be at higher risk for developing insulin resistance compared to other ethnic groups [4]. While some are quick to point out the socioeconomic and cultural features that may lead to these differences, an independent association between ethnicity and disease often remains, even after controlling for dietary and other lifestyle factors.<br />
<br />
In summary, while it is clear that therapeutic lifestyle modifications can have a signficant impact on the development and progression of cardiovascular disease, it is not yet clear how many of these risk factors -- and to what extent -- are under our control. While we should emphasize to patients that healthy lifestyle decisions can be an effective strategy for reducing their risk (which I believe should also include attempts at removing barriers that would prevent them from otherwise making healthy choices), we should recognize that cardiovascular disease may still occur anyway, as it did in the case of former President Bush. Because it is capable of prevailing in the face of even the most intensive lifestyle interventions, cardiovascular disease should be a villain against whom we are all opposed, not as fair and just punishment for a few unhealthy decisions.<br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17387127" target="_blank">Boden WE, O'Rourke RA, Weintraub WS, et al; for the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/23796131" target="_blank">Wing RR, Bolin P, Yanovski SZ, et al; for the Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-54.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/10396605" target="_blank">Gibbs CR, Beevers DG, Lip GY. The management of hypertensive disease in black patients. QJM. 1999 Apr;92(4):187-92.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/12642369" target="_blank">Steinberger J, Daniels SR; for the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young); American Heart Association Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism). Obesity, insulin resistance, diabetes, and cardiovascular risk in children. Circulation. 2003 Mar 18;107(10):1448-53.</a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com0tag:blogger.com,1999:blog-2288088302799633014.post-50596035458398126802013-08-11T15:38:00.000-04:002017-01-20T10:27:11.488-05:00The trouble with diltiazem infusions<i>This post has been updated, and moved to a new blog at the following URL: </i><br />
<a href="http://blogs.pharmacy.umaryland.edu/atrium/2016/03/18/the-trouble-with-diltiazem-infusions/">http://blogs.pharmacy.umaryland.edu/atrium/2016/03/18/the-trouble-with-diltiazem-infusions/</a><br />
<ol>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com10tag:blogger.com,1999:blog-2288088302799633014.post-50277528381195460412013-06-16T18:00:00.000-04:002013-10-10T16:19:15.228-04:00TransitionsI am excited to announce that I have accepted a full-time faculty position at the <a href="http://www.pharmacy.umaryland.edu/" target="_blank">University of Maryland School of Pharmacy</a>, where I will be practicing at the <a href="http://www.umm.edu/" target="_blank">University of Maryland Medical Center</a> in Baltimore, MD. To those of you from the University of North Carolina who have followed this blog from the very beginning, thank you for encouraging me to keep it up. While taking this next step in my career is definitely bittersweet, I am grateful that cardiology remains a small world, and I look forward to opportunities to collaborate in the future.Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-34554359107350664632013-05-21T13:40:00.001-04:002013-05-21T13:40:54.072-04:00Desensitization in patients with an aspirin allergyAfter <a href="https://twitter.com/brentnreed/status/334473604739788800" target="_blank">tweeting</a> about an aspirin desensitization we performed last week, I have received several requests for our approach in patients with aspirin allergies, as well as the protocol that we use to desensitize those in whom we feel therapy is clinically indicated.<br />
<br />
Given the time and resources required for a desensitization (e.g., drug preparation, admission to an intensive care unit, frequency of monitoring, etc.), the most important initial steps are determining if aspirin is indicated (and no other reasonable alternatives exist), and whether the patient has a history of a true type I hypersensitivity reaction (e.g., anaphylaxis) to aspirin. In the case of the former, all of our aspirin desensitizations have been performed for the purpose of providing dual antiplatelet therapy in the setting of an acute coronary syndrome (ACS), often with coronary stent placement. For patients with stable coronary disease (or for those in whom monotherapy may mitigate excess bleeding risk), clopidogrel monotherapy may serve as a suitable alternative to aspirin; based on the results of the CAPRIE trial, clopidogrel is associated with comparable rates of both ischemic and bleeding outcomes compared to aspirin [1]. Unfortunately, the number of patients for whom this would be a reasonable strategy is quite small, making aspirin desensitization necessary in the majority of cases.<br />
<br />
If aspirin is clinically indicated, a thorough interview of the patient should be performed to determine the type of allergic reaction experienced. In many cases, the reported allergy is not a type I hypersensitivity reaction, or it is simply an adverse effect (e.g., gastritis) that has been mislabeled as an allergy. If the history is unclear, or if the patient provides any information that might be concerning (e.g., a rash occurred but unsure whether swelling or wheals were involved, unsure about timing related to exposure, etc.), I usually err on the side of caution.<br />
<br />
At our institution, we transfer patients undergoing aspirin desensitization to the cardiac intensive care unit, where they can receive frequent monitoring of vital signs and observation for adverse reactions. We use the procedure described by Wong, et al. [2] to reach a target dose of 325 mg over a 3-hour period. For the doses preceding 81 mg, we compound a liquid formulation by crushing an 81 mg chewable tablet and mixing it with a sufficient quantity of sterile water to create a 1 mg/mL solution. Additionaly, we compound two batches in case the patient vomits up a dose. <br />
<br />
The desensitization is then performed as follows: <br />
<ol>
<li>Pre-medicate with oral diphenhydramine 25 mg and famotidine 20 mg.</li>
<li>Check vital signs at baseline and every 20 minutes thereafter.</li>
<li>At 20 minute intervals, administer the following doses of aspirin:<br />[Time 00:00] 0.1 mg (0.1 mL)<br />[Time 00:20] 0.3 mg (0.3 mL)<br />[Time 00:40] 1 mg (1 mL)<br />[Time 01:00] 3 mg (3 mL)<br />[Time 01:20] 10 mg (10 mL)<br />[Time 01:40] 20 mg (20 mL)<br />[Time 02:00] 40 mg (40 mL)<br />[Time 02:20] 81 mg (one 81 mg tablet) <br />[Time 02:40] 162 mg (two 81 mg tablets)<br />[Time 03:00] 325 mg (one 325 mg tablet) <br /></li>
<li>After the last dose of the desensitization, a normal administration time (i.e., every 24 hours) may be resumed.</li>
<li>If an allergic reaction is observed at any time, rescue medications (intravenous diphenhydramine, epinephrine) should be administered.</li>
</ol>
We target an initial dose of 325 mg because this is the standard loading dose at our institution for patients presenting with ACS (some institutions use 162 mg for this purpose); however, after achieving this dose during the desensitization process, we then administer a maintenance dose of 81 mg daily.<br />
<br />
<i>Acknowledgement: Special thanks to Abigail Miller Cook, PharmD, BCPS, with whom I collaborated on the above process at our institution; Abbie is currently a clinical pharmacy specialist at <a href="http://www.loyolamedicine.org/" target="_blank">Loyola University Medical Center</a> in Chicago, IL.</i><br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/8918275" target="_blank">CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996 Nov 16;348(9038):1329-39.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/10808182" target="_blank">Wong JT, Maclean JA, Bloch KJ, et al. Rapid oral challenge-desensitization for patients with aspirin-related urticaria-angioedema. J Allergy Clin Immunol. 2000 May;105(5):997-1001.</a></li>
</ol>
<blockquote class="tr_bq">
<br /></blockquote>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-35026375398323620812013-05-12T10:19:00.001-04:002013-06-17T15:40:38.907-04:00Uncharted territory: bivalirudin and the new P2Y12 inhibitorsEarlier this week, we were discussing the evidence to support the direct thrombin inhibitor (DTI) bivalirudin in patients undergoing percutaneous coronary intervention (PCI) and how its use has evolved to include the full spectrum of acute coronary syndromes (ACS) [1-4]. In general, when compared to the combination of unfractionated heparin (UFH) and a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin is associated with similar ischemic outcomes but a lower incidence of bleeding. Given the poor outcomes associated with bleeding after ACS, these characteristics have conferred a very advantageous benefit-risk profile for bivalirudin in the setting of PCI.<br />
<br />
One of the only disadvantages associated with the use of bivalirudin monotherapy is the potential for early stent thrombosis, a phenomenon mostly noted in HORIZONS-AMI, which specifically enrolled patients with ST-segment elevation myocardial infarction receiving early PCI [3]. Although patients randomized to bivalirudin experienced a benefit in net clinical adverse events (9.2% vs. 12.1% with UFH plus GPI, p = 0.005), an increase in stent thrombosis in the first 24 hours was also observed (1.3% vs. 0.3% with UFH plus GPI, p < 0.001). Despite this early difference, rates of stent thrombosis at 30 days were not different between the two groups.<br />
<br />
The most plausible explanation for the early increase in stent thrombosis observed in the bivalirudin group is that many patients were probably not yet experiencing the antiplatelet effects of clopidogrel. Although the onset of action is thought to occur more quickly (around 2 hours) with the 600 mg loading dose, only about two-thirds of patients received this dose prior to PCI. Even at 2 hours, patients randomized to bivalirudin likely experienced a delayed onset of dual antiplatelet therapy compared to those in the UFH plus GPI group, where the onset of GPI therapy would have been almost immediate.<br />
<br />
Despite this potential disadvantage with the use of bivalirudin, the overall net clinical benefit still weighs heavily in its favor, so current practice guidelines recognize it as being an acceptable alternative to heparin (with or without a GPI) in patients undergoing PCI [5]. As a result, bivalirudin has largely supplanted the use of heparin at our institution, as well as many other large PCI centers.<br />
<br />
However, as we have also expanded our use of the newer P2Y12 inhibitors prasugrel and ticagrelor, the thought occurred to me that these two agents have not been extensively studied with bivalirudin. In fact, I was astounded by how little bivalirudin was used in the landmark trials comparing prasugrel and ticagrelor to clopidogrel -- only 3% and 2% in TRITON TIMI 38 and PLATO, respectively [6, 7].<br />
<br />
Given the proposed advantages of these agents compared to clopidogrel (e.g., earlier onset of action, greater potency, no susceptibility to genetic polymorphisms, etc.), one would anticipate that they be at least non-inferior in terms of ischemic outcomes, but do we really know? Prasugrel demonstrated a clear difference in efficacy after only a few hours in its comparison to clopidogrel, but some have attributed at least some degree of this difference to the lower loading dose and delayed administration of clopidogrel in TRITON TIMI 38 [6]. Similar early differences were not observed with ticagrelor, where nearly half of patients were receiving clopidogrel prior to randomization and of those randomized to continue receiving clopidogrel, more received an appropriate loading dose prior to PCI [7]. Interestingly, a recent study of the pharmacodynamic effects of prasugrel and ticagrelor demonstrated that both had fairly poor antiplatelet activity in the hours following an initial loading dose, which makes me wonder just how much of a clinical advantage they provide in the hours immediately following an ACS [8].<br />
<br />
Therefore, should we anticipate improvements in the incidence of stent thrombosis and other thrombotic complications when the new P2Y12 inhibitors are used in combination with bivalirudin? More importantly, are these agents associated with similar rates of bleeding as clopidogrel and bivalirudin (at least when compared to UFH plus a GPI)? While one might anticipate comparable rates of bleeding between clopidogrel and ticagrelor (based on similarities observed in the overall trial), I am not sure we can anticipate this with prasugrel given its higher rates of bleeding and fatal bleeding compared to clopidogrel at baseline.<br />
<br />
Based on the increased uptake of bivalirudin and the new P2Y12 inhibitors, the combination of the two will undoubtedly become a standard of care -- but is it one that we have robustly tested? While I certainly do not believe we are putting patients at excessive risk with the combination of bivalirudin and a newer P2Y12 inhibitor, I am not sure we have much evidence to support it -- and if there is one thing I have learned from practicing in cardiology, it is that placing faith over evidence is one of the quickest ways to get burned.<br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/12588269" target="_blank">Lincoff AM, Bittl JA, Topol EJ, et al; for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003 Feb 19;289(7):853-63.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17124018" target="_blank">Stone GW, McLaurin BT, Ohman EM, et al; for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006 Nov 23;355(21):2203-16. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/18499566" target="_blank">Stone GW, Witzenbichler B, Mehran R, et al; for the HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008 May 22;358(21):2218-30.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/22077909" target="_blank">Kastrati A, Neumann FJ, Mehilli J, et al; for the ISAR-REACT 4 Trial Investigators. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med. 2011 Nov 24;365(21):1980-9.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/22064601" target="_blank">Levine GN, Bates ER, Ting HH, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011 Dec 6;58(24):e44-e122.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17982182" target="_blank">Wiviott SD, Braunwald E, Antman EM, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/19717846" target="_blank">Wallentin L, Becker RC, Thorsén M, et al; for the PLATO investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/23500251" target="_blank">Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) Primary PCI Study. J Am Coll Cardiol 2013; 61: 1601-1606. </a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-69077109211293403102013-05-05T09:26:00.001-04:002017-08-28T20:45:09.128-04:00Cocaine and beta blockers: all it's cracked up to be?<i>This post has been updated, and moved to a new blog at the following URL: </i><br />
<a href="http://blogs.pharmacy.umaryland.edu/atrium/2017/08/29/cocaine-and-beta-blockers-all-its-cracked-up-to-be/">http://blogs.pharmacy.umaryland.edu/atrium/2017/08/29/cocaine-and-beta-blockers-all-its-cracked-up-to-be/</a>Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com3tag:blogger.com,1999:blog-2288088302799633014.post-9191807237539662992013-04-02T19:11:00.000-04:002013-04-03T06:18:30.114-04:00Three's a crowd: WOEST and combination antithrombotic therapyOne of the most challenging scenarios in cardiology is managing the potential risks and benefits of <i>triple therapy</i>, i.e., the combination of dual antiplatelet therapy (DAPT) (aspirin plus a P2Y12 inhibitor) and oral anticoagulation in patients who have indications for both (e.g., percutaneous coronary intervention (PCI) and atrial fibrillation). Although a number of potential management strategies have been proposed (e.g., placing bare metal stents to limit duration of DAPT, targeting a lower INR range, etc.), none are supported by anything beyond retrospective trials or meta-analyses. Ever since preliminary results from the WOEST trial <a href="http://www.theheart.org/article/1439915.do" target="_blank">were announced last year</a> -- a trial comparing triple therapy to the combination of clopidogrel and warfarin alone -- many have been awaiting its full publication to understand how applicable the results would be to clinical practice.<br />
<br />
In WOEST, 573 patients receiving oral anticoagulation with warfarin set to undergo PCI were randomized to warfarin plus clopidogrel alone (i.e., double therapy), or warfarin plus aspirin and clopidogrel (i.e., triple therapy) [1]. Baseline characteristics were fairly well-balanced between the two groups, and the indication for oral anticoagulation was atrial fibrillation/atrial flutter, mechanical heart valves, or other thromboembolic disorders (e.g., pulmonary embolism) in approximately 70%, 10%, and 20% of patients, respectively. At a median follow-up of 365 days, the primary endpoint of any bleeding event within one year of PCI was observed in 19.4% of patients receiving double therapy compared to 44.4% of patients receiving triple therapy (p < 0.0001). No differences in TIMI major bleeding were found. Interestingly, a reduction in the composite secondary endpoint of death, myocardial infarction, stroke, target-vessel revascularization, and stent thrombosis was observed in patients randomized to double therapy (11.1% versus 17.6% with triple therapy, p = 0.025), although the study was not powered to detect differences in this endpoint.<br />
<br />
Although a lot of buzz had been generated about WOEST prior to its publication, I was reluctant to recommend double therapy without knowing more about the patient population enrolled in the trial. After reading the full results, I am actually surprised at how at-risk the patient population was for recurrent thrombotic events (i.e., where the addition of a third antithrombotic agent would be of theoretical benefit). The number of cardiovascular risk factors present among patients enrolled in the trial was representative of contemporary practice, and about a third of patients presented with acute coronary syndrome (ACS). Of the stented lesions, many were fairly high risk, with about 40% of stents being placed in the left anterior descending (LAD) artery, about 30% in the right coronary artery (RCA), and about 25% in the left circumflex (LCx) artery.<br />
<br />
Beyond some of the limitations noted by the study authors (e.g., relatively small size, open-label design, not being powered to detect differences in thrombotic events), I believe the main challenge posed by the WOEST trial will be how to incorporate its results into a standard of practice that is rapidly changing. Whether similar results in bleeding events would be observed with the combination of one of the newer P2Y12 inhibitors prasugrel or ticagrelor and warfarin is not known at this time. Additionally, it is not known whether the new oral anticoagulants apixaban, dabigatran, or rivaroxaban provide the same degree of protection as warfarin in the setting of coronary artery disease. In the case of dabigatran, its use may even be associated with an increased risk of myocardial infarction (further detailed in a <a href="http://reedb.blogspot.com/2012_02_01_archive.html" target="_blank">previous post</a>), a risk that seems at least in part ameliorated in patients also taking aspirin.<br />
<br />
Based on the results of WOEST, I think it is reasonable to consider double therapy with clopidogrel and warfarin alone in a significant number of patients who would have otherwise been candidates for triple therapy. I would especially consider this strategy in the setting of elective PCI. For patients receiving PCI as part of the management of an ACS event (especially myocardial infarction), I am not sure the 30% of patients enrolled in WOEST (i.e., < 200 of the 573 total patients) is enough to justify <i>indiscriminate</i> use of double therapy over triple therapy in this setting. Until a larger study (or one specifically evaluating patients with ACS) is conducted, I think the decision as to which regimen is most appropriate in patients with ACS unfortunately remains a risk versus benefit scenario.<br />
<br />
<i>Thoughts? Should we be using double therapy in this population irrespective of indication (i.e., ACS versus elective PCI)? Please leave your comments below. </i><br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/23415013" target="_blank">Dewilde WJ, Oirbans T, ten Berg JM, et al; for the WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15.</a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com2tag:blogger.com,1999:blog-2288088302799633014.post-61291631849269014532013-03-20T19:35:00.000-04:002013-03-20T19:35:34.828-04:00From the headlines: azithromycin and the risk of fatal arrhythmiasAzithromycin (Zithromax®) <a href="http://newsroom.heart.org/news/fda-warns-public-that-taking-azithromycin-may-lead-to-potential-fatal-irregular-heart-rhythm" target="_blank">made headlines again last week</a> after the US Food & Drug Administration (FDA) issued a safety alert to warn patients and prescribers of an increased risk of fatal arrhythmias associated with its use. As outlined in a <a href="http://reedb.blogspot.com/2012/05/azithromycin-in-patients-with.html" target="_blank">previous blog entry from May</a>, this latest announcement is the result of an investigation by the FDA following an analysis <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1003833" target="_blank">originally published by the New England Journal of Medicine</a> [1], which found an increased risk of sudden cardiac death associated with azithromycin use. At the time, the reason for this increased risk was unknown, but many suspected it was due to QT interval prolongation, a cardiac conduction abnormality already well-described with other macrolide antibiotics. In its latest alert, the FDA warns that azithromycin be avoided in patients with known risk factors for sudden cardiac death, such as a history of arrhythmias or existing QT interval prolongation, hypokalemia, hypomagnesemia, or concomitant antiarrhythmic drug therapy.<br />
<br />
For providers looking for more information about azithromycin use in patients with cardiovascular disease, please see <a href="http://reedb.blogspot.com/2012/05/azithromycin-in-patients-with.html" target="_blank">this previous entry</a>, which outlines alternative management strategies in at-risk patients.<br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1003833" target="_blank">Ray
WA, Murray KT, Stein CM, et al. Azithromycin and the risk of
cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881-90.</a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com2tag:blogger.com,1999:blog-2288088302799633014.post-11162723406256271582013-02-17T18:17:00.002-05:002013-02-17T18:17:43.266-05:00Adjunct antiarrhythmic therapy in refractory ventricular tachycardia: lidocaine versus procainamideFew management decisions are more controversial at my institution than which antiarrhythmic agent to select in patients with ventricular tachycardia (VT) that remains refractory to first-line therapies (e.g., amiodarone, maximally-tolerated doses of beta blockers) or in whom these therapies are contraindicated. In many patients with advanced structural heart disease, lidocaine and procainamide are the only two remaining options. While some renewed enthusiasm for procainamide has emerged as of late -- in part a result of its re-appearance in the <a href="http://circ.ahajournals.org/content/122/18_suppl_3/S729.full" target="_blank">advanced cardiac life support algorithm for VT</a> [1] -- much of the evidence to support procainamide is derived from studies evaluating its use as monotherapy. When used alone, procainamide appears to be more
effective than lidocaine in a heterogenous
patient population [2,3]. However, for a growing number of patients with refractory VT, the challenge facing clinicians is rarely which agent to utilize <i>first </i>(as this is unquestionably amidoarone [4,5]) -- it is which agent to use as <i>adjunct</i> therapy, a scenario where minimal to no data exists to guide clinical decision-making.<br />
<br />
Although many clinicians prefer procainamide for this purpose, I hope to make a case for at least <i>attempting</i> a trial of lidocaine, and why I often favor it as the initial adjunct antiarrhythmic to select in patients with advanced structural heart disease and refractory VT.<br />
<br />
First, several disadvantages of using procainamide in this patient population are worth highlighting. From a pharmacokinetic standpoint, procainamide has a large volume of distribution, requiring that patients receive a considerable loading dose (i.e., 17 mg/kg) to produce a therapeutic effect. Moreover, procainamide and its active n-acetyl metabolite (NAPA) have a longer half-life than lidocaine -- about 3 and 5-8 hours, respectively, in patients with normal metabolic function. These times may be prolonged by as much as five-fold in patients with hepatic and/or renal impairment, conditions that are common in patients with end-stage heart failure. If toxicities (i.e., negative inotropy, hypotension) do emerge following the administration of procainamide, they may persist for extended periods of time, which is especially problematic in patients with compromised baseline hemodynamics. Although monitoring serum concentrations of procainamide and NAPA may ameliorate these risks, few medical centers still perform these tests and the turnaround time for referral assays may take up to a week to produce results. Finally, oral procainamide is no longer available in the US, so in patients for whom a more permanent solution (e.g., cardiac transplantation, ventricular assist device implantation, VT ablation) is not available, procainamide does not represent a long-term management strategy.<br />
<br />
Anecdotally, in the patients with refractory VT that we have treated with procainamide, I have seen at least a third become hemodynamically unstable, many requiring the initiation of inotrope and/or vasopressor therapy and almost all requiring a reduction in their maintenance infusion (often not adequate enough to maintain suppression of the arrhythmia), if not discontinuation of the drug altogether.<br />
<br />
Although lidocaine may be less effective as monotherapy, its use in conjunction with amiodarone has not been evaluated in clinical trials, and the combination may actually produce synergistic antiarrhythmic effects. Theoretically, the addition of lidocaine to amiodarone results in more pronounced blockade of sodium channels (given that lidocaine inhibits both open and inactivated channels) as well as prolongation of the effective refractory period. Furthermore, lidocaine demonstrates enhanced activity in depolarized myocardial cells, a characteristic that is common in ischemic tissue. Given the limited hemodynamic reserve in patients with advanced structural heart disease, the increased myocardial oxygen demand that results from prolonged periods of VT is likely to produce transient periods of ischemia where lidocaine may be especially useful.<br />
<br />
From a pharmacokinetic standpoint, lidocaine has a smaller volume of distribution than procainamide, so smaller loading doses (i.e., 1-1.5 mg/kg) are required to produce a therapeutic response. Moreover, the much shorter half-life of lidocaine (1-2 hours in patients with normal hepatic function) means that if a therapeutic effect is not observed soon after initiation (or if toxicities emerge), the drug is essentially eliminated from the body within hours. While lidocaine may also produce adverse hemodynamic effects, these are more rare at the doses used clinically and are far less pronounced than those observed with procainamide. Finally, if patients <i>do</i> respond to lidocaine and are not candidates for the advanced therapies mentioned above, the drug may be converted to oral mexiletine for chronic maintenance therapy. <br />
<br />
In summary, there is little evidence to guide the management of patients with advanced structural heart disease and refractory VT who are already receiving amiodarone or other antiarrhythmic therapy. Although procainamide appears to be more effective than lidocaine when used as monotherapy, no data exists to compare their adjunct use with amiodarone, a clinical scenario that is becoming more common in patients who are awaiting advanced therapies (or in whom these therapies are not viable). While the advantages of lidocaine in this scenario are largely theoretical (but reasonable based on existing data), it is the arguably the safer of the two drugs in this population, and the only one for which a long-term oral option exists. As a result, unless a more permanent solution for managing refractory VT is already known and imminent, I think it is reasonable to at least attempt a trial of lidocaine as the adjunct antiarrhythmic in most patients.<br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://circ.ahajournals.org/content/122/18_suppl_3/S729.full" target="_blank">Neumar RW, Otto CW, Morrison, LJ, et al. 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science: Part 8: Adult Advanced Cardiovascular Life Support. Circulation. 2010;122:S729-S767. </a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/8712116" target="_blank">Gorgels AP, van den Dool A, Wellens HJ, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol. 1996 Jul 1;78(1):43-6.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/20339190">Komura S, Chinushi M, Aizawa Y, et al. Efficacy of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Circ J. 2010 May;74(5):864-9.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/11907287" target="_blank">Dorian P, Cass D, Barr A, et al. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med. 2002 Mar 21;346(12):884-90.</a></li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/12372573" target="_blank">Somberg JC, Bailin SJ, Molnar J, et al; for the Amio-Aqueous Investigators. Intravenous lidocaine versus intravenous amiodarone (in a new aqueous formulation) for incessant ventricular tachycardia. Am J Cardiol. 2002 Oct 15;90(8):853-9.</a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com2tag:blogger.com,1999:blog-2288088302799633014.post-31113290477460105352013-02-05T19:04:00.002-05:002013-02-05T19:06:39.283-05:00Apixaban management guideline posted to ClotConnectIn early January, the oral factor Xa inhibitor apixaban (Eliquis<sup>®</sup>) became the third novel anticoagulant approved by the FDA for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Several colleagues and I developed <a href="http://professionalsblog.clotconnect.org/2013/02/05/apixaban-eliquis-hospital-guideline/" target="_blank">a guideline</a> for its practical management, which has now been posted to <a href="http://www.clotconnect.org/" target="_blank"><i>ClotConnect</i></a>, an educational website for patients and health care providers developed by Hemophilia and Thrombosis Center at the University of North
Carolina at Chapel Hill. The guideline provides recommendations on the following: <br />
<ul>
<li>Considerations for initiation of therapy (dosing and administration, monitoring parameters, cost considerations)</li>
<li>Conversions to and from other anticoagulants, including
unfractionated heparin, low molecular weight heparin, fondaparinux,
dabigatran, rivaroxaban, and warfarin</li>
<li>Perioperative management </li>
<li>Management of hemorrhagic events</li>
<li>Patient education</li>
</ul>
As was the case with guidelines for the other new oral anticoagulants (dabigatran <a href="http://professionalsblog.clotconnect.org/wp-content/uploads/2011/04/UNC-Pradaxa-5-2012.pdf" target="_blank">here </a>and rivaroxaban <a href="http://professionalsblog.clotconnect.org/wp-content/uploads/2013/01/Rivaroxaban-Management-Guideline-UNC-1-2013.pdf" target="_blank">here</a>), many of the recommendations included in this document have been extrapolated from pharmacokinetic and other pre-clinical investigations, as there is still little other evidence to help guide clinicians in the practical management of these new agents. One can reasonably expect this information to evolve significantly as we gain more practical experience with it and the other new oral anticoagulants. However, in the meantime, we hope this resource will be useful in assisting
other institutions and individual providers who are already using
apixaban in clinical practice.<i> </i><br />
<br />
<i>Special
thanks goes to Ilya Danelich, PharmD, BCPS, who was our cardiology pharmacy resident last year; and <a href="http://professionalsblog.clotconnect.org/" target="_blank">Stephan Moll, MD</a>, for their assistance in the development of this document.</i>Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com0tag:blogger.com,1999:blog-2288088302799633014.post-62016800530024980372013-02-03T18:09:00.000-05:002018-01-13T15:34:49.973-05:00An appeal to avoid atenolol altogetherThis entry has been <a href="http://blogs.pharmacy.umaryland.edu/atrium/2018/01/13/avoiding-atenolol/">moved</a>.<br />
<ol>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-87862785344996114742012-11-03T09:08:00.001-04:002012-11-03T09:08:39.108-04:00The Unit surpasses 10,000 hitsYesterday <i>The Unit</i> surpassed 10,000 hits since its inception a year ago, a benchmark that would not have been possible without the support and encouragement of so many of you. I just wanted to take a moment and thank everyone for reading the blog and/or recommending it to your colleagues -- it's been an incredibly rewarding and professionally-satisfying experience for me. Stay tuned for more!<br />
<br />
<i>If you would like to receive a notification when new entries are posted, you can add my RSS feed <a href="http://reedb.blogspot.com/feeds/posts/default" target="_blank">here</a>, or follow me on <a href="http://twitter.com/brentnreed" target="_blank">twitter </a>or <a href="http://www.facebook.com/people/Brent-Reed/9408537" target="_blank">facebook</a>.</i>Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com0tag:blogger.com,1999:blog-2288088302799633014.post-59735357768394881612012-11-01T14:41:00.000-04:002012-11-02T09:37:50.938-04:00Health care reform and the 2012 ElectionSince I am at home visiting family for the week, I took the opportunity to vote early here in my local precinct rather than mailing in my ballot as I have in previous years. With the presidential election only days away, lines at the booth were encouragingly long, even in this small rural town.<br />
<br />
Although the US economy has largely been the centerpiece of debate between <a href="http://www.barackobama.com/" target="_blank">Barack Obama</a> and <a href="http://www.mittromney.com/" target="_blank">Mitt Romney</a>, health care reform is a close second, with the fate of the Affordable Care Act (ACA) hanging in the balance. As the individual largely responsible for its creation -- not to mention the namesake for "Obamacare", by which the ACA is more commonly (and often derisively) known -- Obama <a href="http://www.barackobama.com/health-care?source=primary-nav" target="_blank">supports extension of the act</a> as part of his second presidential term, while Romney has <a href="http://www.mittromney.com/issues/health-care" target="_blank">pledged to repeal it</a> as early as his first day in office. And the fate of the ACA is only the tip of the iceberg -- the candidates also differ on their views regarding the future of Medicare and Medicaid, the roles and responsibilities of state and federal governments, preventative health, women's health, and more. As Blendon, et al write <a href="http://www.nejm.org/doi/full/10.1056/NEJMsr1211472" target="_blank">in their editorial</a> on the role of health care reform in this election, "rarely [have] two major candidates' views about health care been so diametrically opposed" [1] -- despite the fact that much of the ACA is based on the state health care program that Romney helped create as governor of Massachusetts.<br />
<br />
As is the case with any political issue subject to significant controversy, the conversations surrounding health care reform have largely been monopolized -- and arguably <i>paralyzed </i>-- by the opinions of politicians and pundits of the popular news media, leaving little opportunity for health care professionals to educate themselves on the stark differences between the candidates' platforms. Although more is at stake for health care professionals in this election than perhaps ever before, few resources are available to help compare and contrast the two candidates' views -- at least in a way that is comprehensive and non-partisan. Of note, I did find <a href="http://www.webmd.com/news/breaking-news/candidate-comparison/default.htm" target="_blank">this resource</a> developed by WebMD, which compares several of the most important issues surrounding health care reform (e.g., addressing the rising costs of care, Medicare and Medicaid, women's health, etc.) head-to-head.<br />
<br />
My point is this: without regard to political affiliation, every individual participating in this election -- especially health care professionals -- should assume responsibility for educating themselves on the issue of health care reform, not simply based on the opinions that dominate the airwaves, but based on the details of the two platforms themselves. And even if you vehemently disagree with the views of the opposition, educating yourself on the issue only elevates the level of discussion, which -- no matter the result of the election -- is a win-win for everyone.<br />
<br />
<i>Note: For the purposes of this entry, information was presented in a non-partisan fashion; if you continued reading to see if I would describe my views on the issue (or endorse a particular candidate's position), I would be happy to <a href="mailto:brentreed@gmail.com" target="_blank">discuss further by email</a>. Additionally, if anyone is aware of other helpful resources, please <a href="mailto:brentreed@gmail.com" target="_blank">send them my way</a>, or leave them as comments below. </i><br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.nejm.org/doi/full/10.1056/NEJMsr1211472" target="_blank">Blendon, et al. Understanding health care in the 2012 election. N Engl J Med 2012; 367:1658-1661.</a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com1tag:blogger.com,1999:blog-2288088302799633014.post-80377424473613011782012-10-27T18:07:00.000-04:002012-10-27T18:08:23.322-04:00Clinical pharmacy services: but what shall we call it?The opening session of this past week's <a href="http://www.accp.com/meetings/am12/" target="_blank">2012 Annual Meeting</a> of the <a href="http://www.accp.com/index.aspx" target="_blank">American College of Clinical Pharmacy (ACCP)</a> focused on advancing a comprehensive and consistent practice for clinical pharmacy, a topic that often generates significant -- if not heated -- debate among practitioners and professional organizations alike. In her opening remarks, Dr. Linda Strand, one of four panel members selected to share their perspectives on the topic, laid out what she considers the five "rules" necessary for the success of clinical pharmacy services.<br />
<blockquote class="tr_bq">
In order to be successful, these services must be:<br />
<ol>
<li>Described simply, in terms of what they can do for the patient;</li>
<li>Based on standards of care so that they can be delivered consistently from one practitioner to the next, and from one patient to the next;</li>
<li>Integrated within the rest of the health care team in terms of consistent terminology, philosophy, care process, and standards of practice;</li>
<li>Able to generate measurable results that are reproducible;</li>
<li>Paid for in the same way that other patient care is reimbursed.</li>
</ol>
</blockquote>
<br />
While the latter four rules are all concepts that the whole profession is likely to support, the first, or <i>what shall we call it?</i> is one that we have struggled with for decades. I couldn't help but get the sense that even the four members of the panel did not agree entirely on what we should call it.<br />
<br />
I thought -- perhaps mistakenly -- that we had largely laid this issue to rest with the coining of the term <i>medication therapy management</i>, which was meant to describe clinical pharmacy services in a way that pharmacists, patients, providers, and payers could intuitively understand. This feature gave it several advantages over <i>pharmaceutical care</i>, a term favored by many individuals across the profession of pharmacy, but one that never seemed to catch on outside of it. Unfortunately, <i>medication therapy management </i>coincided with the development of the Medicare Part D benefit (of which it is an integral part), so it has been viewed by many as being only <i>a component</i> of what pharmacists can do rather than the comprehensive services described by the <a href="https://www.accp.com/docs/positions/misc/CoreElements.pdf" target="_blank">Core Elements document</a>, or the consensus definition of <i>medication therapy management</i>, which is already supported by nine national professional pharmacy organizations (including ACCP):<br />
<blockquote class="tr_bq">
<i>A distinct service or group of services that optimizes drug therapy with the intent of improved therapeutic outcomes for individual patients.</i></blockquote>
So rather than moving us forward, I am concerned that reverting back to arguing over what we should call it will only distract us from the most important issues at-hand -- the last four of those five rules necessary for our collective success. While we still have a long way to go, the momentum generated by the <i>medication therapy management</i> movement arguably took us farther in a few years than previous efforts did over the course of decades, largely because it took an idea mostly relegated to members of the pharmacy profession and put it in the minds of the people responsible for consuming it, legislating it, and paying for it.<br />
<br />
And we can't afford to go back now.<br />
<br />
Is <i>medication therapy management</i> the right term? I don't know -- that is for the profession to decide. But we need to decide quickly, because the latter four of Strand's rules may slip through our fingertips while we waste time arguing over what to call it.Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com0tag:blogger.com,1999:blog-2288088302799633014.post-76691725668293143012012-10-14T16:33:00.000-04:002012-10-14T21:09:36.535-04:00TRILOGY ACS: Does it raise new questions about the advantages of prasugrel over clopidogrel?One of the landmark trials to emerge from the proceedings of the <a href="http://www.escardio.org/congresses/esc-2012/pages/welcome.aspx" target="_blank">European Society of Cardiology 2012 meeting</a> was TRILOGY ACS, the long-awaited comparison of prasugrel and clopidogrel in patients with acute coronary syndrome (ACS) for whom a medical management strategy is selected [1]. Prior to its publication, the use of prasugrel was recommended only in patients for whom percutaneous coronary intervention (PCI) was intended, based on the results of TRITON TIMI 38 [2].<br />
<br />
In TRILOGY ACS, patients with unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI) for whom a medical management strategy was selected were randomized to receive prasugrel or clopidogrel, added to background therapy with aspirin. Patients randomized to prasugrel were given a 30 mg loading dose followed by 10 mg daily, and patients over the age of 75 or under 60 kg were given 5 mg daily (a maintenance dose already available but previously unstudied in large clinical trials). Patients randomized to clopidogrel received a 300 mg loading dose followed by 75 mg daily, a regimen already known to reduce cardiovascular events in a similar patient population [3]. The primary analysis of TRILOGY ACS was intended for those patients under the age of 75, while analyses for older patients were only exploratory.<br />
<br />
No differences in the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke were observed (13.9% versus 16.0%, p = 0.21), a stark contrast to the results of TRITON TIMI 38. Interestingly, no significant differences in bleeding events were observed either, although this may have been due to the use of lower prasugrel maintenance doses in older and lower weight patients, two groups that were at higher risk of bleeding complications in previous trials.<br />
<br />
While patients enrolled in TRILOGY ACS were unquestionably different from those included in TRITON TIMI 38 (e.g., no PCI performed, patients with ST-elevation myocardial infarction [STEMI] excluded), for me, this trial raises several questions about the long-term advantages of prasugrel over clopidogrel, even in those patients for whom an invasive strategy is selected.<br />
<br />
First, nearly 95% of patients in TRILOGY ACS were pre-treated with clopidogrel prior to randomization, with the majority of them receiving at least 4 days of therapy. Based on the results of TRITON TIMI 38, where significant benefit was observed in the first few days after randomization, some might contend that the window for observing maximal benefit with prasugrel was missed, as patients randomized to prasugrel did not receive it until several days after their index event. On the other hand, it may also indicate that there is minimal to no incremental benefit with the use of prasugrel in patients who are already receiving dual antiplatelet therapy, a hypothesis previously untested in earlier trials.<br />
<br />
Which brings me to my next point -- how the lack of benefit observed in TRILOGY ACS highlights several important limitations in the design of TRITON TIMI 38 and how it may have given prasugrel an unfair advantage over clopidogrel in the PCI population.<br />
<br />
As mentioned above, much of the proposed benefit of prasugrel in TRITON TIMI 38 was observed in the first few hours after randomization, with nearly half of the 2.2% difference in the primary endpoint being observed at only 3 days after randomization (5.6% versus 4.7%, or a difference of 0.9%, p = 0.01) [2]. While the appearance of these differences so early in the trial have been cited as one of the major advantages of prasugrel, a couple of important limitations should also be considered:<br />
<ul>
<li><b>Clopidogrel loading dose</b>. While the appropriate loading dose of clopidogrel prior to PCI remains somewhat controversial, current guidelines recommend 600 mg, as this dose has demonstrated a faster onset of antiplatelet activity, a reduction in cardiovascular events at 30 days (a difference that emerges only days after randomization), and minimal (if any) differences in bleeding compared to a 300 mg loading dose [4]. However, patients in TRITON TIMI 38 only received a 300 mg loading dose prior to PCI, a practice that probably represented the standard of care at the time but is now thought to be inferior to a 600 mg loading dose.</li>
<li><b>Timing of clopidogrel administration</b>. One of the major pharmacokinetic advantages of prasugrel is that its antiplatelet effects emerge as early as 30 minutes after oral administration (peak of around 4 hours). For clopidogrel, even at doses of 600 mg, these effects do not emerge until around 2 hours. In TRITON TIMI 38, nearly 75% of patients received their loading doses during PCI (or immediately thereafter), so it is unlikely that the antiplatelet effects of clopidogrel were even realized in the first few hours after randomization.</li>
</ul>
So it should be no surprise that such a significant difference in efficacy emerged as soon as hours after randomization. However, the question is -- can those differences be attributed to prasugrel being a superior drug, or was clopidogrel simply not administered early enough (or at an appropriate dose) to observe its beneficial effects? <br />
<br />
Furthermore, we now know that genetic variations in the expression of CYPC19 correspond to differences in clopidogrel response, likely due to a reduction in the biotransformation of clopidogrel to its active metabolite. Carriers of at least one CYP2C19 reduced-function allele (*2 or *3) are less responsive to clopidogrel when compared to non-carriers (wild-type, or *1). A cohort of patients receiving clopidogrel in TRITON TIMI 38 were genotyped for loss-of-function alleles (n = 1477); of the patients who were carriers of a loss-of-function allele (i.e., non-responders), the primary endpoint occurred in 12% compared to only 8.0% of non-carriers (i.e., responders) (p = 0.01), a result comparable to the incidence observed with prasugrel in the overall population. Similar results were observed for stent thrombosis, where 2.6% of carriers experienced an event compared to only 0.8% of non-carriers (p = 0.02) [5]. <br />
<br />
In summary, I believe TRILOGY ACS raises several important questions about the advantages, and thus, the cost-effectiveness, of prasugrel for the long-term management of ACS, irrespective the management strategy selected (i.e., invasive or medical management). The trial I would like to see performed is one that compares prasugrel to an adequate loading dose of clopidogrel (600 mg) administered at least 1-2 hours prior to PCI; all patients would be genotyped to see if any differences could be attributed to CYP2C19 polymorphisms. <br />
<br />
That being said, I do think prasugrel has some pharmacokinetic advantages over clopidogrel and should be considered first-line in certain clinical scenarios. For example, I think it should be considered over clopidogrel in patients who require immediate revascularization (e.g., STEMI) or in other high-risk patients for whom the delayed onset of antiplatelet activity observed with clopidogrel might pose a risk to therapeutic outcomes. However, would that same patient continue to derive benefit from the use of prasugrel in the long-run (versus transitioning to clopidogrel)?<br />
<br />
Of that I am the most doubtful, but will probably never know for sure.<br />
<br />
<b>References</b><br />
<ol>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/22920930" target="_blank">Roe MT, Armstrong PW, Ohman EM, et al; for the TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012 Oct 4;367(14):1297-309.</a> </li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17982182" target="_blank">Wiviott SD, Braunwald E, Antman EM, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15.</a> </li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/11519503" target="_blank">Yusuf S, Zhao F, Fox KK, et al; for the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502.</a> </li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/17010792" target="_blank">Cuisset T, Frere C, Alessi MC, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol. 2006 Oct 3;48(7):1339-45. </a> </li>
<li><a href="http://www.ncbi.nlm.nih.gov/pubmed/19106084" target="_blank">Mega JL, Close SL, Sabatine MS, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. </a></li>
</ol>
Brent N Reedhttp://www.blogger.com/profile/11029165152109465961noreply@blogger.com0