The Unit: A Cardiology Blog: acute coronary syndromes

Showing posts with label acute coronary syndromes. Show all posts

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

Tuesday, May 21, 2013

Desensitization in patients with an aspirin allergy

After tweeting 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.

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.

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.

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.

The desensitization is then performed as follows:

Pre-medicate with oral diphenhydramine 25 mg and famotidine 20 mg.
Check vital signs at baseline and every 20 minutes thereafter.
At 20 minute intervals, administer the following doses of aspirin:
[Time 00:00] 0.1 mg (0.1 mL)
[Time 00:20] 0.3 mg (0.3 mL)
[Time 00:40] 1 mg (1 mL)
[Time 01:00] 3 mg (3 mL)
[Time 01:20] 10 mg (10 mL)
[Time 01:40] 20 mg (20 mL)
[Time 02:00] 40 mg (40 mL)
[Time 02:20] 81 mg (one 81 mg tablet)
[Time 02:40] 162 mg (two 81 mg tablets)
[Time 03:00] 325 mg (one 325 mg tablet)
After the last dose of the desensitization, a normal administration time (i.e., every 24 hours) may be resumed.
If an allergic reaction is observed at any time, rescue medications (intravenous diphenhydramine, epinephrine) should be administered.

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.

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 Loyola University Medical Center in Chicago, IL.

References

Sunday, May 12, 2013

Uncharted territory: bivalirudin and the new P2Y12 inhibitors

Earlier 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.

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.

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.

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.

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].

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].

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.

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.

References

Sunday, May 5, 2013

Cocaine and beta blockers: all it's cracked up to be?

This post has been updated, and moved to a new blog at the following URL:
http://blogs.pharmacy.umaryland.edu/atrium/2017/08/29/cocaine-and-beta-blockers-all-its-cracked-up-to-be/

Tuesday, April 2, 2013

Three's a crowd: WOEST and combination antithrombotic therapy

One of the most challenging scenarios in cardiology is managing the potential risks and benefits of triple therapy, 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 were announced last year -- 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.

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.

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.

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 previous post), a risk that seems at least in part ameliorated in patients also taking aspirin.

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 indiscriminate 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.

Thoughts? Should we be using double therapy in this population irrespective of indication (i.e., ACS versus elective PCI)? Please leave your comments below.

References

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.

Sunday, February 3, 2013

An appeal to avoid atenolol altogether

This entry has been moved.

Sunday, October 14, 2012

TRILOGY 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 European Society of Cardiology 2012 meeting 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].

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.

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.

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.

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.

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.

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:

Clopidogrel loading dose. 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.
Timing of clopidogrel administration. 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.

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?

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].

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.

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)?

Of that I am the most doubtful, but will probably never know for sure.

References

Monday, September 3, 2012

Update: Deja vu in ATLAS ACS-2: rivaroxaban in the subset of patients with ST-segment elevation myocardial infarction

In an article posted on theheart.org last week highlighting the results of several late-breaking clinical trials revealed at the 2012 European Society of Cardiology (ESC) meeting, experts again debated the utility of adding low-dose rivaroxaban (2.5 mg twice daily) to dual antiplatelet therapy in patients with acute coronary syndromes (ACS). The discussion involved a pre-specified sub-analysis of ATLAS ACS 2 [1], a trial that randomized patients with ACS who were already receiving aspirin and clopidogrel to either rivaroxaban or placebo. A sub-analysis of the patients with ST-segment elevation myocardial infarction (STEMI) found a small but marginally significant reduction in major adverse cardiovascular events (absolute risk reduction 1.9%, HR 0.81 (95% CI 0.65-1.00), p = 0.047) with rivaroxaban. However, as observed in the overall cohort of patients with ACS, this benefit was accompanied by a significant increase in several types of bleeding (details unavailable at this time).

As I describe in a previous entry on the results of ATLAS ACS 2, I am still not sure it is worth pursuing the addition of rivaroxaban in patients with ACS until we know its risk versus benefit profile in combination with aspirin and one of the newer P2Y12 inhibitors prasugrel or ticagrelor. Although, given the results of another trial revealed at ESC 2012, perhaps we should be dropping aspirin from the "triple therapy" strategy anyway.

What is perhaps an even more challenging scenario, as the article goes on to discuss, is what to do when patients have multiple indications for anticoagulation or are already receiving rivaroxaban for a different indication and have an ACS event. The appropriate dose of rivaroxaban depends on indication -- 10 mg once daily for prophylaxis of venous thromboembolism following major orthopedic surgery, 15 mg twice daily for the treatment of deep vein thrombosis or pulmonary embolism (assuming the agent will be approved for these indications based on the results of the two EINSTEIN investigations [2,3]), or 20 mg daily for atrial fibrillation (15 mg once daily if impaired renal function). If someone has an ACS event that requires dual antiplatelet therapy and is already taking rivaroxaban for one of these indications, do we reduce the dose to 2.5 mg twice daily given that higher doses are already known to increase the risk of bleeding in this population [4]?

I suppose nobody has any definitive answers to these and other challenging clinical scenarios that will soon be at our doorstep, but one thing I do know for sure -- what an exciting time to be practicing in the area of cardiology.

Note: the 2.5 mg twice daily dose of rivaroxaban was up for approval by the US Food & Drug Administration earlier this year, but failed to gain the indication for use in acute coronary syndromes.

References

Saturday, July 21, 2012

Just a little heart attack: supporting the Go Red for Women campaign

During her review of the initial management of acute coronary syndromes in my Advanced Cardiac Life Support (ACLS) course this afternoon, Paula Miller shared with us the video posted below, produced by the American Heart Association as part of its Go Red for Women campaign. The goal of Go Red for Women is to raise awareness of cardiovascular disease as the number one cause of death among women -- more deaths than all types of cancer combined. As part of the campaign, women are encouraged to understand their risk of cardiovascular disease and recognize the signs and symptoms of heart attack and stroke, which often present differently in women than in men.

Although chest pain or pressure remains the most common symptom of heart attack, women are more likely to experience other symptoms, including:

Lightheadedness
Shoulder or jaw pain
Nausea or vomiting
Shortness of breath
Breaking out in a cold sweat

The signs and symptoms of stroke are generally similar in men and women and include:

Confusion
Dizziness
Loss of balance
Changes in speech
Numbness or tingling in the face, arms, or legs, especially on one side of the body

You can read more about the signs and symptoms of heart attack and stroke here.

Entitled "Just a Little Heart Attack", the video stars Elizabeth Banks as a multitasking mother of two who is busy juggling her career and household while virtually ignoring an ongoing heart attack -- a perfect illustration for why the Go Red for Women campaign is so important. I found it well-done and entertaining and thought I would share:

Saturday, February 18, 2012

Dabigatran and myocardial ischemia: a pharmacologic perspective

In RE-LY, the landmark trial comparing dabigatran (Pradaxa^®) and warfarin in patients with atrial fibrillation, the investigators observed an increased risk of myocardial infarction (MI) among patients randomized to dabigatran [1]. Although the increased risk was only numerically different in patients randomized to the lower dose of dabigatran (110 mg), the higher dose (150 mg) group met the threshold for statistical significance (relative risk 1.38, CI 1.00 - 1.91, p = 0.048). Since the original publication of RE-LY, the subject of increased ischemic risk associated with dabigatran has been a topic of heated debate. Two analyses published last month look at this issue in greater depth [2, 3].

In a sub-analysis of the original RE-LY trial [2], Hohnloser, et al found a numerical but not statistically significant difference in the annual risk of MI among patients randomized to dabigatran -- why this is different from the original trial is still a mystery to me, but I'll attribute it to how small the difference was in the original trial. Outcomes were similar among the subgroup of patients with a known history of coronary artery disease (CAD) and a pre-specified analysis of net clinical benefit -- a composite of ischemic, thrombotic, and hemorraghic events -- also favored dabigatran (p = 0.02).

However, in a meta-analysis of seven trials comparing dabigatran to standard therapy in atrial fibrillation, acute coronary syndromes, or venous thromboembolism [3], Uchino, et al observed a small but statistically significant risk of MI associated with dabigatran therapy (absolute risk 0.14% - 0.17%, p = 0.03). Results were similar when the revised data from RE-LY were included and when trials of shorter duration were excluded.

Most have contended that the increased risk attributed to dabigatran is due to the protective effects of warfarin rather than an adverse effect of dabigatran. After all, warfarin improves outcomes post-MI and is more effective than aspirin for this indication [4]. However, given the difficulty of managing warfarin in such an extensive patient population, dual antiplatelet therapy has become the preferred standard of care in the majority of post-MI patients.

While the authors of these trials do not propose a pharmacologic basis for the potential risk of ischemic events associated with dabigatran therapy, I think a signal observed in an earlier trial may provide a few clues. In PETRO [5], the first trial to evaluate dabigatran in patients with atrial fibrillation, patients were randomized to one of three doses of dabigatran (alone or in combination with aspirin) or adjusted-dose warfarin. In the patients randomized to dabigatran, investigators observed an unexpected increase (17-31%) in the urinary excretion of 11-dehydrothromboxane B2 (DTB₂), a byproduct of thromboxane A₂ and a marker of platelet activation. Thromboxane A₂ is a pro-inflammatory mediator responsible for platelet activation and aggregation and is implicated in the pathogenesis of acute coronary syndromes. The inhibition of thromboxane A₂ production is thought to be the mechanism by which aspirin exerts its beneficial effects in patients with ischemic heart disease. Interestingly enough, the urinary excretion of DTB₂ in patients taking dabigatran was attenuated (by 40-57%) in those patients that were also on aspirin.

If the DTB₂ excretion observed in patients on dabigatran is responsible for the increased rates of ischemic events attributed to the drug, this could be responsible for the discrepancies observed between the RE-LY sub-analysis and the meta-analysis conducted by Uchino, et al. Given the association between ischemic disease and atrial fibrillation, approximately 40% of the patients in RE-LY were also taking aspirin, a percentage that may have been sufficient enough to dilute the rates of ischemic disease that may have otherwise been observed. If this is truly the case, it is not surprising that increased rates were not observed among patients with CAD, as the vast majority of them were likely on aspirin.

Although the incidence of CAD was not reported among patients enrolled in other trials included in the meta-analysis, I anticipate it was low given the heterogeneity of the patient population (with the exception of the single trial of patients with acute coronary syndromes). As a result, fewer of these patients would have been on concomitant aspirin therapy and would not have obtained a potential protective effect of aspirin. Because more of these non-aspirin patients were included in the meta-analysis, it may have been enough to signal an increased risk of MI with dabigatran use.

Although this is entirely speculative, I do think it is important to at least recognize a plausible pharmacologic explanation for the increased risk of ischemic events attributed to dabigatran if such an effect actually exists. The issue is unlikely to be resolved without a prospective analysis -- a recommendation made by the authors of both publications. While I do not anticipate an investigation to be performed any time soon, I hope one will at least address the aspirin issue at some point in the future, as this could change how we manage patients on dabigatran therapy. In other words, should we also be placing the majority of them on aspirin?

References

Tuesday, December 6, 2011

Deja vu in ATLAS ACS 2: rivaroxaban in acute coronary syndromes

Another major trial that emerged out of the 2011 American Heart Association meeting last month was ATLAS ACS 2 [1], which evaluated the addition of rivaroxaban (Xarelto^®) to dual antiplatelet therapy in patients with acute coronary syndromes (ACS). A reduction in major cardiovascular events was demonstrated in the group randomized to rivaroxaban therapy, but this benefit was accompanied by an increase in major nonfatal bleeding.

The rationale behind ATLAS ACS 2 is similar to WARIS II [2], a study conducted in 2002 which randomized patients to aspirin, warfarin, or both following an acute myocardial infarction (MI). The study demonstrated that warfarin given alone or in combination with aspirin reduced major cardiovascular events (largely driven by reductions in reinfarctions and thromboembolic strokes) but was associated with an increase in major nonfatal bleeding. However, the practice never really caught on. First, the addition of warfarin seemed impractical and inconvenient for the majority of patients who presented following an MI. Secondly, as the results of WARIS II were being finalized, the CURE trial was published [3], paving the way for dual antiplatelet therapy as the new standard of care in patients with ACS. Given the follow-up and monitoring required for long-term warfarin therapy, the addition of clopidogrel to aspirin seemed like a more attractive strategy for reducing major cardiovascular events following ACS. Since that time, no robust randomized prospective trials have specifically investigated the addition of warfarin to dual antiplatelet therapy for the purpose of improving outcomes in ACS, so the practice was largely abandoned before it ever began.

Given the complex thrombotic risk associated with ACS, the addition of rivaroxban was expected to provide a similar benefit as warfarin in WARIS II, but without the cumbersome monitoring and follow-up required (and perhaps a lower incidence of certain types of bleeding) -- but given the evolution of antiplatelet therapy, is ATLAS ACS 2 simply a case of deja vu?

In ATLAS ACS 2, rivaroxaban was added to dual antiplatelet therapy comprised of aspirin and clopidogrel (and in a few instances, ticlopidine). However, some would argue that we have entered an era where clopidogrel will be gradually phased out in favor of the newer antiplatelet agents prasugrel (Effient^®) and ticagrelor (Brillinta^®) (or, at the very least, its use will be primarily reserved for the minority of patients who are not candidates for other therapies). While I anticipate this process will take years to occur, several recently published guidelines already reflect this shift in practice -- the 2011 European guidelines for non-ST elevation myocardial infarction (NSTEMI) recommend prasugrel and ticagrelor as first-line therapy in appropriate patients and the 2011 US guidelines for percutaneous coronary intervention (PCI) recommend these agents as reasonable alternatives to clopidogrel.

So, while the addition of low-dose rivaroxaban appeared to benefit patients in ATLAS ACS 2, is this simply the modification of a standard of care that is already on its way out? Prasugrel is clearly associated with increased rates of bleeding versus clopidogrel. While ticagrelor is associated with a similar incidence of bleeding overall, it had higher rates of bleeding in certain key subgroups, including intracranial hemorrhage and non-CABG related major bleeding. Therefore, given the incidence of bleeding already associated with newer antiplatelet therapies, the risks of adding rivaroxaban to these emerging standards of care may actually outweigh its benefits. Moreover, if a clinician's reasoning for avoiding prasugrel or ticagrelor in a specific patient is related to concerns for bleeding, the addition of long-term rivaroxaban seems even more unlikely.

With the patent for clopidogrel set to expire late in the second quarter of next year, it will likely remain a standard of care for many patients in the US for some time. If patients who would otherwise be candidates for prasugrel or ticagrelor are placed on clopidogrel for financial considerations, I cannot imagine any financially justifiable advantages of adding rivaroxaban -- an agent that will probably only be available as a brand name product for the next decade or more.

Either way, it is still too early to tell how ATLAS ACS 2 will influence the management of patients with ACS. However, if history (i.e., WARIS II) has taught us anything, the addition of rivaxoban in patients with ACS may also be a practice that is abandoned before it ever begins...

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