The Unit: A Cardiology Blog: perspectives

Showing posts with label perspectives. Show all posts

Saturday, January 11, 2014

Digoxin, digoxout: an appraisal of digoxin immune fab

Preface: The inspiration for this topic came from an exchange on Twitter between @PharmERToxGuy, @DavidJuurlink, and I, representing one of the things I love most about #hcsm -- the opportunity for dialogue across diverse backgrounds and practice settings. In this particular case, we debated the appropriate use of digoxin immune fab (DigiFab^®), 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.

My reasons for advocating the conservative use of digoxin immune fab (DigiFab^®) 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.

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 dysrhythmia), 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].

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].

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].

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.

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].

That being said, the following are situations where I would definitely recommend the use of digoxin immune fab:

Ventricular arrhythmias, accelerated junctional rhythms
Life-threatening bradyarrhythmias unresponsive to chronotropic agents (and when temporary pacing is not readily available)
Acute mental status changes
Acute overdose

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 toxic 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.

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.

Peer review: Special thanks goes to Jo Ellen Rodgers, PharmD, FCCP, BCPS (AQ Cardiology), a clinical associate professor at the University of North Carolina Eshelman School of Pharmacy, and Jonathan Cicci, PharmD, BCPS, a clinical pharmacy specialist in cardiology at the University of North Carolina Health Care for their review of this entry.

References

Saturday, August 17, 2013

Perspectives on the Bush stenting case: lifestyle modifications and the risk of cardiovascular disease

Significant controversy (examples here, here, and here) 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 John M's blog) and more importantly, how living a healthy lifestyle is not always the be-all end-all strategy for reducing one's cardiovascular risk.

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.

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.

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 daily limit of sodium 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].

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.

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.

References

Sunday, August 11, 2013

The trouble with diltiazem infusions

This post has been updated, and moved to a new blog at the following URL:
http://blogs.pharmacy.umaryland.edu/atrium/2016/03/18/the-trouble-with-diltiazem-infusions/

Saturday, November 3, 2012

The Unit surpasses 10,000 hits

Yesterday The Unit 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!

If you would like to receive a notification when new entries are posted, you can add my RSS feed here, or follow me on twitter or facebook.

Thursday, November 1, 2012

Health care reform and the 2012 Election

Since 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.

Although the US economy has largely been the centerpiece of debate between Barack Obama and Mitt Romney, 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 supports extension of the act as part of his second presidential term, while Romney has pledged to repeal it 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 in their editorial 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.

As is the case with any political issue subject to significant controversy, the conversations surrounding health care reform have largely been monopolized -- and arguably paralyzed -- 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 this resource 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.

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.

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 discuss further by email. Additionally, if anyone is aware of other helpful resources, please send them my way, or leave them as comments below.

References

Blendon, et al. Understanding health care in the 2012 election. N Engl J Med 2012; 367:1658-1661.

Saturday, October 27, 2012

Clinical pharmacy services: but what shall we call it?

The opening session of this past week's 2012 Annual Meeting of the American College of Clinical Pharmacy (ACCP) 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.

In order to be successful, these services must be:

Described simply, in terms of what they can do for the patient;

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;

Integrated within the rest of the health care team in terms of consistent terminology, philosophy, care process, and standards of practice;

Able to generate measurable results that are reproducible;

Paid for in the same way that other patient care is reimbursed.

While the latter four rules are all concepts that the whole profession is likely to support, the first, or what shall we call it? 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.

I thought -- perhaps mistakenly -- that we had largely laid this issue to rest with the coining of the term medication therapy management, 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 pharmaceutical care, a term favored by many individuals across the profession of pharmacy, but one that never seemed to catch on outside of it. Unfortunately, medication therapy management 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 a component of what pharmacists can do rather than the comprehensive services described by the Core Elements document, or the consensus definition of medication therapy management, which is already supported by nine national professional pharmacy organizations (including ACCP):

A distinct service or group of services that optimizes drug therapy with the intent of improved therapeutic outcomes for individual patients.

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 medication therapy management 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.

And we can't afford to go back now.

Is medication therapy management 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.

Wednesday, October 3, 2012

Selecting an oral anticoagulant in patients with atrial fibrillation: an evidence-based guide for clinicians

Choosing the most appropriate oral anticoagulant has become a challenging decision in the management of patients with atrial fibrillation and one that often generates significant discussion on rounds. Unfortunately, no trial has compared all of the available options head-to-head, so data must be extrapolated from several sources, all while attempting to incorporate patient-specific characteristics that might make one strategy better than another. Because the topic comes up so frequently, I developed the following algorithm to help guide my recommendations and thought I would share.

This information is also available in PDF format.

Figure 1. Evidence-based algorithm for choosing an oral anticoagulant in atrial fibrillation (Click image for a larger version)
Abbreviations: OACs oral anticoagulants, GI gastrointestinal, CAD coronary artery disease, INR international normalized ratio, CrCl creatinine clearance

Clinical Rationale (also included in the PDF)
Each point below corresponds to a section of the algorithm shown above.

For patients with a known history of atrial fibrillation (AF), decisions regarding oral anticoagulation should consider previous management strategies, including relative degree of success. Evidence indicates that patients who are successfully anticoagulated with warfarin may continue to do well with warfarin compared to those who are newly initiated on therapy or transitioned to other agents [1,2]. Notably, this trend has not been observed in patients transitioned from warfarin to the higher dose (150 mg) of dabigatran [3].
In the landmark trials comparing the new oral anticoagulants (OACs) rivaroxaban or dabigatran to warfarin, the mean INR time in therapeutic range (TTR) for patients randomized to warfarin ranged from 55% to 64% [2,3]. A mean TTR in the mid-60% range is generally considered the gold standard when comparing an agent to warfarin, which explains why the low TTR observed in ROCKET-AF was such a major criticism of the trial. While a mean TTR in the mid-60% range represents the global management of patients on warfarin therapy, some centers are able to achieve much higher mean TTR values. How successfully a patient has been (or could be) managed on warfarin therapy should be factored into management decisions, as none of the new OACs have been compared to warfarin in patients with higher TTR ranges.
Patients who have been successfully managed on warfarin therapy should still be presented with the option of transitioning to a new OAC if they find the monitoring and lifestyle restrictions (e.g., diet) associated with warfarin therapy to be inconvenient. Most guideline authorities recognize the importance of including patients in this management decision. However, the limitations of these new agents (many of which are included in this document) should be fully disclosed to patients prior to making a decision about anticoagulation therapy.
The following is a list of several important limitations with the new OACs.

Valvular heart disease. Patients with valvular heart disease were specifically excluded in the major trials comparing the new OACs with warfarin. Because these patients are generally at higher thromboembolic risk (especially those with certain types of prosthetic valves), it is unknown whether the new OACs provide a degree of anticoagulation comparable to warfarin in these settings.
Extreme body weights (< 60 kg or > 120 kg). The mean body weight of patients in the trial comparing dabigatran to warfarin was 82.5±19.4 kg and the mean BMI of patients in the trial comparing rivaroxaban to warfarin was 28 ± 3 kg/m²; patients at the very extremes of these body weight ranges have not been well-studied [2,3]. Doses of other anticoagulants (e.g., enoxaparin) are adjusted by weight, so it is unknown whether the new OACs provide a comparable degree of anticoagulation in patients with extremely low or high body weights at the fixed doses studied in randomized trials.
History of significant gastrointestinal hemorrhage. In the trials comparing rivaroxaban or dabigatran to warfarin, both agents were associated with significantly increased rates of gastrointestinal hemorrhage. While this fact is a well-known adverse effect of dabigatran, some clinicians may be unaware that similar risks were observed with rivaroxaban.
Active or advanced liver disease. Patients with active or advanced liver disease, including those with evidence of coagulopathy (e.g., elevated INR at baseline), were excluded from major trials comparing the new OACs to warfarin. Furthermore, rivaroxaban undergoes significant hepatic metabolism and is known to accumulate in patients with significant hepatic impairment [4].
Dual antiplatelet therapy for coronary artery disease required. Few patients on dual antiplatelet therapy (i.e., aspirin plus a P₂Y₁₂ receptor inhibitor) were included in the major trials comparing the new OACs to warfarin [2,3]. Of those that were, few if any were on the combination of aspirin and prasugrel (a combination associated with a higher risk of major and fatal bleeding at baseline) and none were on ticagrelor. Therefore, for patients at a lower risk of stroke and in whom the risk of bleeding associated with the addition of warfarin is thought to outweigh the potential benefit, it may be reasonable to use only dual antiplatelet therapy for the critical period after the index event (including whether a coronary stent was placed) and then transition to warfarin after that time. While the combination of aspirin and clopidogrel is inferior to warfarin for stroke prevention in the setting of atrial fibrillation, it does provide some degree of protection while these patients are recovering from an acute event [1,5]. For patients with a higher risk of stroke due to atrial fibrillation, it may be reasonable to use the combination of aspirin, a P₂Y₁₂ inhibitor, and warfarin targeted to a less aggressive INR goal (i.e., 2 – 2.5), a recommendation recently incorporated into management guidelines for non-ST segment elevation myocardial infarction [6]. Emerging data indicates that these patients may also be safely managed with a P₂Y₁₂ inhibitor and warfarin alone, although these results have not been fully published nor included in clinical practice guidelines.
Other conditions. Patients with other conditions that may influence drug metabolism (e.g., advanced heart failure), where monitoring of anticoagulation status may be necessary to ensure ongoing safety, should still be considered for warfarin therapy. Use of currently available measurements of anticoagulation status (e.g., prothrombin time, ecarin clotting time, activated partial thromboplastin time, etc.) to guide therapy with the new OACs has not yet been well-validated.

Cost is an important consideration when initiating therapy with a new OAC, as issues related to access and ability to pay are some of the most significant contributors to patient non-adherence. The new OACs are generally more expensive than warfarin, even for patients with health insurance and prescription drug coverage, including (in most cases) when the expenses associated with warfarin monitoring and follow-up are also considered. The manufacturers of the new OACs have some financial assistance programs available, and these should be considered for those patients who are unlikely to do well with warfarin but who are also unable to afford a new OAC.
Renal impairment may be the most important limitation with the use of the new OACs.

End-stage renal disease. Both dabigatran and rivaroxaban should be avoided in patients with severe renal impairment (creatinine clearance [CrCl] < 15 mL/min) due to the risk of drug accumulation.
Severe impairment. Patients with moderate renal impairment (CrCl 15-60 mL/min) may be considered for therapy with a new OAC. While an adjusted dose of dabigatran is available in those patients with some degree of renal impairment (CrCl 15-30 mL/min), data to support its use is derived from pre-clinical trials and pharmacokinetics rather than prospective evidence. Therefore, this guideline recommends rivaroxaban in those patients, as the dose adjusted for renal impairment (15 mg daily, for CrCl 15-50 mL/min) was included in the large trial comparing it to warfarin [2].
Moderate impairment. For patients with moderate renal impairment, age should become an additional consideration regarding which new OAC to choose, as equations commonly used to predict renal function are far less accurate in older patients, especially those with low body weight (i.e., muscle mass). The inaccuracy of these equations may help explain why increased rates of hemorrhage have been observed with dabigatran in older patients (see additional explanation in Part G below).
Mild impairment or normal. For patients with normal renal function or only mild renal impairment, dabigatran should be used preferentially over rivaroxaban, as it showed clinical superiority to warfarin in the large randomized control trial comparing the two agents. At a dose of 150 mg twice daily, dabigatran demonstrated improvements in the composite endpoint of stroke and systemic embolism (as well as several secondary endpoints) with a comparable degree of overall bleeding and less bleeding in several key subgroups (including intracranial hemorrhage). On the other hand, rivaroxaban was shown as only being non-inferior to warfarin in the primary analysis of its comparison trial with a lower incidence of overall bleeding. Therefore, this guideline gives preference to dabigatran, except in cases where its advantages over warfarin are less likely (e.g., renal impairment, older age), making rivaroxaban a more ideal choice.

As mentioned above, estimates of renal function are less predictable as patients age. As a result, older patients with adequate renal function (as predicted by the Cockcroft-Gault or other equations) may actually have a significant degree of renal impairment. In these patients, the risk of accumulation with dabigatran may outweigh its potential benefits, making rivaroxaban a more ideal choice. Additionally, a post hoc analysis of the RE-LY trial as well as pooled data from adverse event reports indicates that the risk of major bleeding associated with dabigatran increases significantly in older patients.7 Although various age thresholds for avoiding dabigatran have been proposed (e.g., > 75 years, > 85 years), the median age of patients experiencing adverse events with dabigatran is around 80 years, so this threshold was chosen for this tool. Even if patients have normal renal function or mild impairment, caution should still be exerted when initiating dabigatran in patients over the age of 80 years given the limited ability to estimate renal function in this patient population.

Note: Some contend that the once daily dosing of rivaroxaban provides it with a significant clinical advantage to dabigatran, especially in patients with poor medication adherence. However, this is not yet supported by the literature and may be a risky proposition given the increased rates of thromboembolic events observed in patients transitioning from rivaroxaban to warfarin following the conclusion of ROCKET-AF [2]. Additionally, it is generally thought that medication adherence is not significantly impacted until patients are required to take medications three times a day and many patients with atrial fibrillation are already taking other medications twice daily (e.g., certain beta blockers, antiarrhythmics, antihypertensives, etc.). Finally, based on pharmacokinetic comparisons between dabigatran and rivaroxaban (e.g., duration of action, termination half-life), dabigatran may provide a similar degree of thromboembolic protection compared to once daily rivaroxaban even if doses are missed (although this is not yet based on evidence from the literature).

As always, comments and suggestions (and disagreements, of course!) welcomed.

References

Sunday, September 16, 2012

PILL-CVD: Clinical services and keeping ourselves honest

Given the increasing cost and complexity associated with health care delivery, a variety of stakeholders from across the continuum of care (e.g., hospitals, health systems, third party payers, state and federal government agencies) have launched exhaustive efforts to identify strategies that improve outcomes as patients transition from the health care environment to home. Challenges related to medication use -- from cost to compliance to adverse drug events -- serve as a key area of emphasis, especially given their contribution to patient injury and hospital readmissions. For example, adverse events related to medication therapy have been associated with patient injury in up to 40% of hospitalized patients and nearly 20% of patients following discharge [1,2]. Given the expertise of pharmacists in the area of medication safety, many see us as being the health care professionals responsible for leading efforts aimed at overcoming these challenges. A number of initiatives have been investigated as a result, including medication reconciliation at admission and/or discharge, discharge counseling and education, telephone follow-up, and more.

Recently, the PILL-CVD trial [3] was designed to evaluate whether a combination of these strategies would reduce the number of clinically important medication errors in patients being discharged after an acute coronary syndrome or heart failure exacerbation. Patients (n = 851) were randomized to usual care or a pharmacist-based intervention that included discharge medication reconciliation, discharge counseling, and individualized telephone follow-up after discharge. Although clinically important medication errors were discovered in over half of the patients enrolled in the study, intervention by a pharmacist failed to reduce them when compared to usual care. Patients in the intervention group tended to have fewer potential adverse drug events, but even this difference was not statistically significant.

There were certainly limitations of the study, many of which were discussed by the authors. For example, patients were enrolled at two large academic medical centers, where robust medication reconciliation systems may have made it difficult to demonstrate a difference in the intervention group. Additionally, the patient population was relatively well-educated and demonstrated a high level of health literacy, which may have also impacted outcomes.

While the results of PILL-CVD may have rustled some feathers, I can accept it because I think it helps keep us honest. Our clinical activities should be just as evidence-based as the therapies we recommend, especially in light of the rising costs of care and the already limited resources in pharmacy and beyond. We should support, extend, and improve those activities that optimize patient outcomes and abandon those that do not. Where some may see the results of PILL-CVD as a threat to the role of pharmacists in transitions of care, I instead see it as a call to re-focus on those initiatives that do improve medication therapy outcomes, some of which were already included in this study.

As one example, pharmacists in the acute care setting are ideally positioned to perform comprehensive medication reconciliation at discharge. To clarify, I share the view that discharge medication reconciliation is not simply the generation of a medication list, but is instead a vital component of medication therapy management -- that is, an interdisciplinary strategy aimed at optimizing the medication regimen of each individual patient -- an effort that has been associated with improvements in both clinical and economic outcomes in a variety of settings [4]. As such, medications should not be evaluated solely on the basis of whether or not the patient was receiving them during their hospitalization, but whether it is appropriate to continue them based on factors that include safety, efficacy, cost, and compliance.

On the other hand, I maintain that medication counseling performed by acute care pharmacists at the point of discharge is not a very effective -- nor efficient/sustainable -- strategy for improving medication-related outcomes. While small studies have shown some improvements compared to usual care, differences are marginal at best and other studies have shown no impact at all. When I provide discharge medication counseling, I often see individuals and families who are exhausted, buried in paperwork, and overwhelmed with information... but even more importantly, I see people who are eager to leave the hospital. The last thing they want is for yet another health care professional to provide them with even more information they will soon forget -- and understandably so -- in their hurry to get things together and prepare for discharge. So I reluctantly hand them another stack of handouts to file away in a folder along with their discharge summary, upcoming appointments, laboratory results, medication list, etc.

While this may seem discouraging, it just reminds me to remain focused on those activities that do improve patient outcomes, including:

Rounding in the intensive care unit [5];
Rounding with a cardiology medicine service [6];
Collaborative management of anticoagulation [7], blood pressure [8], dyslipidemia [9], and other cardiovascular risk factors [10]; and,
Improving medication adherence among high-risk patients [11].

So while the results of PILL-CVD may have been concerning for some, I am encouraged that it will lead us to explore new or alternative strategies for improving medication-related outcomes as patients make the transition to the ambulatory care environment. Given significantly limited resources across health care settings and providers who are already stretched thin, it is important that we hold ourselves accountable for performing those clinical activities that are best supported by the available evidence -- even if it means leaving behind some activities that we once held dear.

Comments welcomed and encouraged.

References

Friday, August 3, 2012

Shopping around: variations in price for generic clopidogrel

In May of this year, the patent for brand-name clopidogrel (Plavix^®) finally expired, an event that was heralded as a breakthrough in the management of coronary artery disease. As with all newly available generic medications, months may pass before generic clopidogrel becomes considerably less expensive than its brand name counterpart. As generic manufacturers scramble to ramp up production, significant differences in price and availability are likely.

These differences were recently highlighted in the September issue of Consumer Reports, where a variety of pharmacies across the US were surveyed on the price of a 30-day supply of clopidogrel. The prices ranged anywhere from $15 to $200 -- notably, independent pharmacies consistently quoted a price of around $50, which was often markedly lower than many of their chain and supermarket competitors.

The article also mentions the Plavix^® Choice program, which allows patients to obtain brand-name Plavix^® through the manufacturer at a significantly reduced cost -- $37 in most cases. Significant restrictions apply, of course; for example, only commercially-insured and cash-paying patients (i.e., no Medicare or Medicaid enrollees) are eligible for the program. Although the article goes on to claim that the manufacturer picks up the difference, it is not clear from the Bristol-Myers Squibb website that this is the case. When the patent for brand-name atorvastatin (Lipitor^®) expired in the fall of last year, Pfizer was widely criticized for several controversial financial arrangements with pharmacy benefit managers (PBMs), including a prescription discount program aimed at retaining market share. Although the program provided some cost-savings for patients, insurers and health-systems were often stuck paying the bill.

In the end, the editors of Consumer Reports recommend that patients "shop around" for generic clopidogrel. However, as most health care professionals will say, shopping around is rarely the right answer in the long run. Patients should obtain all of their medications at a single community pharmacy (or pharmacy chain/franchise), as this allows the pharmacist to maintain a complete and accurate medication record, which is critical for evaluating drug-food and drug-drug interactions (see here for an example), responding to requests for medication information from other health care providers, assisting in medication reconciliation when patients are hospitalized, and more. Besides, most pharmacies already offer competitor price-matching programs, so no one should need to obtain their clopidogrel prescription anywhere other than their home pharmacy.

So while it is appropriate to recommend that patients ask around for the lowest price of generic clopidogrel, they should still be encouraged to shop in only one place.

Friday, May 25, 2012

Overcoming the drug shortage challenge: a call to action

For providers working in hospital and health-system settings, drug shortages have become an unfortunate reality of every day practice. While the lay media has placed much of its emphasis on cancer chemotherapy and other drugs used in oncology practice, cardiology and critical care medicine are two areas that have been hit especially hard by drug shortages. In the last six months, the following intravenous medications have been subject to extended periods of limited to no availability:

Analgesics (fentanyl, morphine)
Antibiotics (aminoglycosides, fluoroquinolones)
Antihypertensives (hydralazine)
Antiarrhythmics (lidocaine, procainamide)
Beta blockers (labetalol, metoprolol)
Benzodiazepines (diazepam, lorazepam, midazolam)
Calcium channel blockers (diltiazem)
Loop diuretics (furosemide, bumetanide)
Nutrition and electrolytes (magnesium, phosphate, sodium bicarbonate)
Vasopressors (epinephrine, vasopressin)
... and many more (antiemetics, other sedatives)

The underlying reasons for these critical drug shortages are complex and multifactorial, and which ones deserve the most blame are largely subject to one's political and economic views. Some have argued that the shortages are a result of failures in the free market, i.e., when a manufacturer decides that a product is no longer profitable, they can cease production without regard to whether patients depend on it or not. Others argue that the regulatory environment enforced by the US Food & Drug Administration (FDA) is too strict and has made it challenging for companies to stay competitive. The truth is probably somewhere in between, but no matter how you feel about the issue, the consequences are the same: drug shortages significantly impact patient care.

On Thursday, the Senate passed the Food and Drug Administration Safety and Innovation Act of 2012 (S.3187), which reauthorizes the Prescription Drug User Fee Act (PDUFA) and includes several provisions designed to help alleviate drug shortages, including:

Expedited review of generic drug approvals;
Incentives for new generic drug manufacturers to enter the market; and,
Early notification to FDA if an interruption in production is anticipated or production is being discontinued altogether.

The House is expected to vote on their version of the bill next week. In the meantime, I encourage you to contact your representatives and urge their support for PDUFA, including those provisions specifically designed to address drug shortages. If you are unsure who these individuals are for your area, please use this free resource developed by the American Society of Health-System Pharmacists (ASHP). Also, for general information and tips for political advocacy, see this toolkit developed by the American Pharmacists Association (APhA).

Tuesday, March 27, 2012

Surrogate markers: reflections of efficacy or only graven images?

I ran across this article the other day, in which Richard Lehman, a British physician and blogger for BMJ, reviews highlights from several popular medical journals. At the end, he cites an article entitled The Idolatry of the Surrogate [2], where Yudkin, et al present an excellent discussion of the controversies surrounding the use of surrogate markers of efficacy versus hard clinical outcomes. The article by Yudkin, et al uses diabetes as an example, but the same argument could be made for many of the markers commonly used in cardiovascular clinical practice (e.g., low-density lipoprotein, carotid intima media thickness, etc).

One of the best parts of Lehman's piece is his citation of Yudkin's Ten Commandments, a section that did not actually make it into the Idolatry piece due to concern over potential religious sensitivities. I found its omission unfortunate, as it is one of the best anecdotes on clinical practice I have read in a while and one I wanted to share:

The New Therapeutics: Ten Commandments

Thou shalt treat according to level of risk rather than level of risk factor.
Thou shalt exercise caution when adding drugs to existing polypharmacy.
Thou shalt consider benefits of drugs as proven only by hard endpoint studies.
Thou shalt not bow down to surrogate endpoints, for these are but graven images.
Thou shalt not worship Treatment Targets, for these are but the creations of Committees.
Thou shalt apply a pinch of salt to Relative Risk Reductions, regardless of P values, for the population of their provenance may bear little relationship to thy daily clientele.
Thou shalt honour the Numbers Needed to Treat, for therein rest the clues to patient-relevant information and to treatment costs.
Thou shalt not see detailmen, nor covet an Educational Symposium in a luxury setting.
Thou shalt share decisions on treatment options with the patient in the light of estimates of the individual’s likely risks and benefits.
Honour the elderly patient, for although this is where the greatest levels of risk reside, so do the greatest hazards of many treatments.

Those of you who follow my blog regularly know that this topic is one of my favorite to debate, as I think it is one of the most controversial in all of professional practice. In the vast majority cases, I tend to side with Yudkin's arguments -- I believe the above considerations lead one to think more critically about a patient's overall risk and the potential for benefit (or additional risk) with any given intervention. Unfortunately, this is often met with some initial resistance, as these arguments rarely fall in line with recognized practice guidelines.

But, as the analysis by Smith, et al in 2009 pointed out, only about a tenth of the recommendations made in cardiology guidelines are based on randomized controlled trials -- the remaining majority are based on small or limited patient populations and over half from expert consensus or standards of care [2].

... which only makes this topic worth debating again and again.

References