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

1. 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.
2. 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.
3. Gibbs CR, Beevers DG, Lip GY. The management of hypertensive disease in black patients. QJM. 1999 Apr;92(4):187-92.
4. 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.

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/

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:

1. Pre-medicate with oral diphenhydramine 25 mg and famotidine 20 mg.
2. Check vital signs at baseline and every 20 minutes thereafter.
3. 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)
   
4. After the last dose of the desensitization, a normal administration time (i.e., every 24 hours) may be resumed.
5. 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

1. 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.
2. 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.

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

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.

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/

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

1. 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.

An appeal to avoid atenolol altogether

This entry has been moved.

New monoclonal antibody REGN727: more effective than statins?

Speaking of surrogate endpoints, I ran across the following headline in Daily Briefing, an e-newsletter I receive as part of my membership in the American Society of Health-System Pharmacists (ASHP): Experimental Drug May Be More Effective Than Statins.

The headline links to several published reports (including this one on theheart.org) about REGN727, an investigational human monoclonal antibody to proprotein convertase subtilisin/kexin 9 (PCSK9). According to the article, PCSK9 is a serum protease involved in the breakdown of hepatic low-density lipoprotein (LDL) receptors.  As a result of antibody-mediated inhibition of PCSK9 by REGN727, hepatic LDL receptors are spared, leading to subsequent reductions in serum LDL concentrations.  At the 2012 American College of Cardiology meeting earlier this week, lead investigators said REGN727 could be a potential "game changer" in the management of dyslipidemia, although a significant amount of research would still be required before the agent becomes available in the US.

In these early phase I trials, a subcutaneous injection of REGN727 was effective at reducing LDL concentrations by up to three-fourths, even in patients already taking maximally-tolerated doses of atorvastatin. Notably, the studies were conducted in healthy volunteers and were not powered to detect differences in clinical outcomes (e.g., cardiovascular morbidity and mortality).

While the drug may be effective at reducing serum LDL concentrations, questions remain as to whether these effects impart significant improvements in cardiovascular outcomes, as we have seen several recent examples where this correlation does not exist.  One investigation in particular is ARBITER 6-HALTS, which compared extended-release niacin (Niaspan^®) to ezetimibe (Zetia^®) and found that, despite being more effective at reducing LDL concentrations, ezetimibe was inferior to niacin at reducing cardiovascular events [1].

So, is this new agent promising? Yes. Is it worth further investigation? Of course.  Alternatives are limited for patients who continue to have progressive atherosclerosis despite maximally-tolerated doses of statins and other antidyslipidemic medications. But to say REGN727 "may be more effective" than statins is a bit of a stretch at this time. Statins do reduce serum LDL concentrations, but they also improve cardiovascular outcomes independently of their effects on LDL, even in patients with cholesterol in the accepted "normal" range.  Whether REGN727 is also able to do this -- independently of its effects on serum LDL concentrations -- is yet to be seen, but is what I think will determine its overall clinical utility in the management of atherosclerotic disease.

 References

1. Taylor AJ, Villines TC, Turco M, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26;361(22):2113-22.

Optimizing strategies for preventing contrast-induced nephropathy

Unfortunately, the motivation for writing this entry was not for the purpose of sharing the findings of a new study, but rather the critical nationwide shortage of sodium bicarbonate, which has left us carefully scrutinizing our strategies for preventing contrast-induced nephropathy (CIN) in patients undergoing cardiac catheterization. For those of you working in a health-system setting, your practice has probably been severely hampered by the growing number of shortages across several therapeutic areas -- hopefully the results from the following study will alleviate some concerns about the need for sodium bicarbonate in the prevention of CIN.

Contrast-induced nephropathy is an unfortunate risk of coronary angiography and it is especially high among patients with existing renal impairment.  Given the extensive use of angiography to evaluate coronary artery disease, strategies to prevent or reduce the risk of CIN have been the subject of ongoing research and unfortunately, the options remain limited.  Oral N-acetylcysteine is no longer recommended (see a summary of the 2012 guidelines for percutaneous coronary intervention here), which leaves intravenous fluid hydration as one of the few remaining alternatives for renoprotection in the setting of cardiac catheterization.  However, the optimal agent recommended for this purpose (i.e., normal saline versus sodium bicarbonate) has not been well-established.

In a study published in late January, Klima, et al [1] randomized 258 patients with renal impairment undergoing intravascular contrast procedures to one of three hydration strategies:

1. Sodium chloride 0.9% (i.e., normal saline) 1 mL/kg/h for at least 12 hours before and after the procedure
2. Sodium bicarbonate (166 mEq/L) 3 mL/kg for 1 hour before and 1 mL/kg/h for 6 hours after the procedure; or,
3. Sodium bicarbonate (166 mEq/L) 3 mL/kg over 20 minutes before the procedure plus oral sodium bicarbonate (500 mg per 10 kg)

Sodium chloride was shown to be superior to sodium bicarbonate at reducing the primary endpoint of change in estimated glomerular filtration rate (eGFR); it was also more effective at reducing the development of CIN, defined as an increase in serum creatinine (SCr) of > 25% or an increase of > 0.5 mg/dL from baseline.  Moreover, the shorter infusion of sodium bicarbonate (20 minutes) plus oral sodium bicarbonate was just as effective as the 7-hour infusion for improving these same endpoints.  No differences were observed in long-term morbidity and mortality or progression to renal replacement therapy.

But does the present study indicate superiority of sodium chloride over sodium bicarbonate?

Not really.

I think the results of this trial only confirms what we've suspected for a long time -- the more hydration around a procedure, the lower the risk of CIN.  That being said, I do think this adds some helpful information to the longstanding debate over which strategy is best for reducing the risk of CIN in the setting of intravascular contrast procedures.

Previous investigations have been rife with limitations.  Furthermore, differences in the types of procedures performed, study populations, and types of contrast dyes utilized have only further complicated efforts to identify a conclusive strategy for renoprotection.  In a recent meta-analysis by Meier, et al, sodium bicarbonate was found to be more effective at reducing CIN; however, effects were less dramatic among patients receiving elective procedures or those receiving iso-osmolar contrast dyes [2].  Another commonly cited study was conducted by Merten et al, where the 7-hour sodium bicarbonate infusion used in the present study was shown to be superior to a 7-hour infusion of sodium chloride [3].  In both instances, no differences in mortality or progression to renal replacement therapy were observed.

I find some comfort in the results of this trial, as it provides us with an alternative for preventing CIN in the setting of a critical nationwide sodium bicarbonate shortage.  However, one remaining question is how long is long enough?  Twelve hours of sodium chloride before and after an intravascular contrast procedure may be more effective than 7 hours of sodium bicarbonate (1 hour before and 6 hours after), but what if the need for catheterization was more urgent (i.e., 4-6 hours or less prior to procedure)? For emergent procedures (i.e., where only < 1 hour of renoprotective measures can be provided prior to procedure), I think we are still compelled to use sodium bicarbonate in the absence of any data stating otherwise.

Secondly, what about patients with moderate to severe heart failure, where excessive intravenous fluid administration could result in clinical decompensation?  Patients with New York Heart Association Class III-IV heart failure were excluded from the present study, and rightly so -- a patient weighing only 70 kg would have received > 1.5 L within a 24-hour period, i.e., definitely enough fluid to promote an exacerbation in a patient with existing heart failure at baseline. In this particular scenario, I think sodium bicarbonate would still be the most attractive option for renoprotection. 

Finally, another interesting finding from the present study is that the shorter course of sodium bicarbonate (20 minutes prior to procedure) combined with oral sodium bicarbonate was just as effective as the 7-hour infusion.  I imagine this strategy would be an attractive option in a number of scenarios, including elective and outpatient intravascular contrast procedures.

At the very least, I think the study by Klima, et al provides us with evidence to support the use of sodium chloride in patients for whom an intravascular contrast procedure is not urgent or emergent.  For these latter scenarios, sodium bicarbonate still appears to be the better option, although it may not be one we can actually use as a result of the ongoing shortage nationwide.  In this case, it appears our only alternative is to hydrate with sodium chloride as much as possible prior to procedure and at least 12 hours afterwards and then hope for the best.


For more information on drug shortages and strategies for addressing them, please see the Drug Shortages Resource Center created by the American Society for Health-System Pharmacists.

References

1. Klima T, Christ A, Mueller C, et al. Sodium chloride vs. sodium bicarbonate for the prevention of contrast medium-induced nephropathy: a randomized controlled trial. Eur Heart J. 2012 Jan 19.
2. Meier P, et al. Sodium bicarbonate-based hydration prevents contrast-induced nephropathy: a meta-analysis. BMC Med. 2009 May 13;7:23.
3. Merten GJ, Burgess WP, Kennedy TP, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004 May 19;291(19):2328-34.

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

1. Connolly SJ, Ezekowitz MD, Wallentin L, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51.
2. Hohnloser SH, Oldgren J, Connolly SJ, et al. Myocardial Ischemic Events in Patients With Atrial Fibrillation Treated With Dabigatran or Warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) Trial. Circulation. 2012 Feb 7;125(5):669-76.
3. Uchino K, Hernandez AV. Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials. Arch Intern Med. 2012 Jan 9.
4. Hurlen M, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-74.
5. Ezekowitz MD, Reilly PA, Wallentin L, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol. 2007 Nov 1;100(9):1419-26.

Little HOPE for ACE inhibitors in revascularized patients

In an analysis recently published in the American Heart Journal, Kalavrouziotis et al found that the use of post-operative angiotensin-converting enzyme (ACE) inhibitors in coronary artery bypass graft (CABG) surgery was not associated with an improvement in survival or rehospitalizations. In fact, significant improvements were only observed in the subgroup of patients with diabetes, where ACE inhibitors were associated with a small but statistically significant reduction in mortality.

Although the trial was a retrospective review of prescription claims data, it continues a trend of investigations that have found little to no benefit with ACE inhibitors in patients whose coronary artery disease (CAD) has been managed with revascularization (i.e., percutaneous coronary intervention or CABG) and who have their cardiovascular risks aggressively managed with concomitant therapies (e.g., antiplatelet therapy, statins, and beta blockers). It also adds to the results observed in IMAGINE, a trial conducted in 2008 that found that the early post-operative use of ACE inhibitors in CABG did not improve cardiovascular outcomes. If anything, it may have even worsened outcomes, given that a pre-specified sub-analysis of the first 3-months found that ACE inhibitors were actually associated with a 50% increase in risk. However, some critics have argued that ACE inhibitors were started too early in the post-operative course (a median of about 4 days) and this may have contributed to the increased risks.

Perhaps one of the first clinical trials to question the routine use of ACE inhibitors in stable CAD was PEACE (2004), where trandolapril failed to reduce major cardiovascular events compared to placebo. This finding contradicted the results of two earlier trials, HOPE (2000) and EUROPA (2003), where ACE inhibitors were associated with significant improvements in cardiovascular events. In one of the most intriguing comparisons among clinical trials to date, the failure of PEACE to show a significant benefit has largely been attributed to its baseline patient population rather than the actual impact of ACE inhibitors on clinical outcomes. When one compares the baseline characteristics of patients enrolled in HOPE, EUROPA, and PEACE, several interesting trends emerge. First, a higher percentage of patients in PEACE were revascularized (PCI or CABG). Secondly, more patients in PEACE were receiving concomitant medications to manage cardiovascular risk (i.e., antiplatelet agents, beta blockers, and lipid-lowering drugs).

In an era where every health care dollar is carefully scrutinized and clinical decision-making is more often based on what patients can afford rather than what is best supported by the evidence, it may be time to re-examine the use of ACE inhibitors in low-risk patients with CAD. Because there are so many indications where ACE inhibitors have shown benefit, I think we get into the habit of prescribing them for almost everyone with CAD.

Although I have joked that everyone could probably use a little ACE inhibition, I have found myself being far more selective in whom I recommend the addition of an ACE inhibitor. After all, ACE inhibitors did not just fail to show a benefit in PEACE -- they actually increased the number of adverse effects. Given the growing body of evidence that shows little to no benefit with their use in low-risk patients, perhaps we should be asking ourselves the same question in every patient with stable CAD -- "Does this patient look more like HOPE or more like PEACE?"

SATURN: Is a statin a statin?

As reported on the heart.org earlier this week, preliminary results from the Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) trial demonstrated no significant differences between the impact of atorvastatin (Lipitor^®) and rosuvastatin (Crestor^®) on the study's primary endpoint, percent atheroma volume (PAV), as measured by intravascular ultrasound (IVUS). Of note, the trial was not powered to detect significant differences in clinical outcomes, such as mortality or major adverse cardiovascular events.

Unless further analysis of SATURN reveals any additional differences, I am not sure SATURN answers the question of which statin (and at what dose) is most appropriate in patients with established coronary artery disease (CAD). The trial that primarily raised thise question was the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) investigation, which showed that atorvastatin 80 mg ("intensive" lipid-lowering therapy) was superior to pravastatin 40 mg ("standard" lipid-lowering therapy) for preventing the composite endpoint of death and other cardiovascular outcomes (e.g., myocardial infarction, stroke, need for revascularization).

As we would expect, atorvastatin 80 mg had a greater impact on low-density lipoprotein (LDL), one of the primary markers for atherosclerosis (and thus cardiovascular risk), so a question that has remained from the PROVE-IT trial is whether improvement in the primary endpoint was due primarily to a reduction in LDL, or if other (commonly called "pleiotropic") effects were at work. One of the arguments supporting the pleiotropic hypothesis was that the difference between the two agents began to emerge as early as 30 days, which is unlikely a consequence of aggressive LDL reduction. If the latter is true, was this due to differences between the individual agents themselves or was it their relative potency, i.e., does a dose threshold exist where these pleiotropic effects begin to have a clinically meaningful impact?

The difference between statins has primarily been an issue for clinicians because of their relative cost; for many of the patients we see at our institution, cost exerts significant influence on clinical decision-making. Pravastatin is generic and available on most discount prescription programs (e.g., $4 dollar lists), so we are often satisfied if patients can be discharged on any statin they can afford, even if it is not the one for which we have the best data -- especially for patients who are already stuck paying for brand-name clopidogrel (Plavix^®) or prasugrel (Effient^®). That being said, choosing among statins may be less of an issue when atorvastatin becomes generically available later this year.

Because rosuvastatin is even more potent than atorvastatin at the higher end of its dosing range, some might argue for its use in some patients, a decision that is not yet supported by the literature. Given the preliminary results to date, SATURN does not appear to indicate which is better, although there may not be as meaningful a difference between the two after all. Even if rosuvastatin had shown a greater impact on PAV as measured by IVUS, the use of this marker as a surrogate for clinical outcomes has not yet been established... but that's another discussion altogether.