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.

Sunshine laws for physicians proposed... but what about Pharmacy Benefit Managers (PBMs)?

An article posted recently on the medical news site amednews.com highlights new regulations being considered by the Centers for Medicare & Medicaid Services (CMS) that would require pharmaceutical companies to disclose any financial ties to physicians.  Commonly known as sunshine laws, these regulations are meant to promote transparency and limit the influence of the pharmaceutical industry on clinical practice.  Many academic medical centers have already enacted strict rules on these relationships, some even going as far as having "zero tolerance" policies.

What I find strangely missing from these regulations, however, are rules requiring pharmaceutical companies to reveal their financial dealings with pharmacy benefit managers (PBMs), the third party intermediaries responsible for negotiating drug prices on behalf of health insurance beneficiaries.  Examples include CVS Caremark, Medco, and Express Scripts -- companies that, despite the impending financial crisis facing US health care, consistently rank among the country's most profitable enterprises (all three are ranked among the top 100).  The financial relationships between these companies and the pharmaceutical industry have been the subject of growing public scrutiny, and rightly so.  While PBMs purport to pass the savings earned from the deals they negotiate with pharmaceutical companies on to beneficiaries, there have been numerous instances where these savings have only increased profit margins for the PBMs themselves.

For an example of how these relationships can impact patients and the overall health care system, one only has to look back a month at the controversies that emerged out of the patent expiration for Lipitor^® (atorvastatin), the best-selling drug of all time. Ever since its patent expired in November, Pfizer has gone to unprecedented lengths to protect its market share.  As detailed in this article from the New York Times, some of the arrangements Pfizer has negotiated with PBMs include:

• Requiring community pharmacies to reject prescriptions for generic forms of atorvastatin and only dispensing brand-name  Lipitor^®
• Reducing the insurance copay for brand-name Lipitor^® to $4 in an effort to undercut the anticipated $10 or so its generic rivals would cost patients
• Requiring that PBM mail order services dispense only brand-name  Lipitor^®

As one might expect, these tactics have raised a lot of eyebrows, including those of Senators Baucus (D-MT), Grassley (R-IA), and Kohl (D-WI), who recently submitted letters to Pfizer and five of the country's largest PBMs asking them to reveal the details of these financial relationships.  The PBMs implicated in the letter have assured legislators that they would not reap the benefits of these negotiations at the expense of patients, their employers, or CMS.

The part I find most unfortunate about this entire ordeal is that it took the media breaking the story as well as several high-profile legislators asking questions before these financial dealings were made public.  No matter how you feel about the Affordable Care Act or health care reform in general, I think we can all agree that there is little to be lost from increased transparency within the health care system.  If CMS is proposing sunshine laws as a strategy for accomplishing this, PBMs should be held to the same standards as individual physicians and the pharmaceutical industry.

After all, if there's truly nothing to hide, what would a little sunshine hurt anyway?

Highlights from the 2011 Guidelines for Percutaneous Coronary Intervention (PCI)

While a significant portion of the 2011 update to the ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention (PCI) [1] focus on revascularization strategies, several important medication changes are also worth highlighting, including the following:  

Aspirin 81 mg is reasonable for chronic maintenance therapy following PCI. Clinicians should no longer feel bound to use higher maintenance doses of aspirin following PCI, as the 2011 guidelines now recognize 81 mg as being an adequate dose for long-term maintenance therapy in patients who have received a loading dose of 325 mg.

Prior to this most recent update, higher doses of aspirin were recommended for a specific length of time based on the type of stent placed.  This practice was largely conventional (i.e., based on the dosing strategies used in stenting trials), rather than evidence indicating higher doses were more efficacious. In fact, a meta-analysis from Antithrombotic Trialists' Collaborative [2] indicated that higher doses were probably associated with more harm than good, although few trials had looked specifically at lower aspirin doses and even fewer included significant numbers of patients receiving PCI.  However, the practice of using higher maintenance doses of aspirin had been all but abandoned outside of North America, a fact further highlighted in the controversy that erupted following the publication of PLATO, where higher aspirin doses were thought to attenuate the effects of ticagrelor in North American patients [3].

Interestingly, the trial that appeared to put the aspirin dosing issue to rest (CURRENT OASIS-7) is not referenced in the updated guidelines. As I summarized in a previous post, CURRENT OASIS-7 demonstrated in a randomized prospective fashion that higher doses of aspirin were not associated with improved outcomes in patients with acute coronary syndromes with or without PCI [4].  

Clopidogrel remains a cornerstone in the management of patients receiving PCI. Although prasugrel and ticagrelor may be selected as an alternative to clopidogrel, the latter remains a mainstay of dual antiplatelet therapy.  Each agent is given a similar recommendation in patients receiving stents (Class I, Level of Evidence B), which differs from the 2011 European guidelines for the management of non-ST segment elevation myocardial infarction (NSTEMI), where clopidogrel is recommended only in those patients who are not candidates for prasugrel or ticagrelor.  With the patent for clopidogrel set to expire in the late spring of 2012, it will undoubtedly remain popular in the US for quite some time.

The results of CURRENT OASIS-7 are again omitted from the 2011 PCI guidelines during the discussion of clopidogrel dosing, where no mention of double-dose clopidogrel (150 mg) for days 2-7 following PCI can be found (despite a Class IIb recommendation for this practice in the US 2011 update to the UA/NSTEMI guidelines). 

Ticagrelor recognized as an alternative to clopidogrel for the first time in the US. As described above, the 2011 PCI guidelines recognize ticagrelor as an alternative to clopidogrel following PCI, marking its first formal inclusion in US guidelines.   

Dual antiplatelet therapy recommended for at least 12 months following PCI. The appropriate duration of dual antiplatelet therapy is recognized as being at least 12 months in this most recent update, with shorter durations acceptable for patients at increased risk of bleeding or in whom bare metal stents are used.  Given the recognizable risk of very late stent thrombosis (i.e., > 1 year from implantation) associated with drug-eluting stents, longer durations may be considered, although no formal length of time is provided.   

Provisional use of intravenous glycoprotein IIb/IIIa inhibitors remains an option in patients not being anticoagulated with bivalirudin. The use of glycoprotein IIb/IIIa inhibitors is recommended in patients who are not being anticoagulated with bivalirudin, with stronger evidence to support this practice in patients who have not already been adequately loaded with clopidogrel.  Adding to the evidence that emerged from the REPLACE-2 and ACUITY trials, the combination of unfractionated heparin (UFH) and a glycoprotein IIb/IIIa inhibitor was shown in ISAR-REACT 4 to be no better than bivalirudin alone in patients with NSTEMI being managed with an early invasive strategy and receiving an adequate loading dose of clopidogrel [5].  Notably, the combination of UFH and a glycoprotein IIb/IIIa inhibitor was also associated with a nearly two-fold increase risk of major bleeding compared to bivalirudin alone.   

The administration of high-dose statins should be considered prior to PCI. It has already been known for some time that high-dose statins are associated with improved outcomes early in the management of acute coronary syndromes.  However, the results of the NAPLES II trial [6] indicate that some of these improvements may be observed as early as hours after PCI, only adding to the evidence that high potency statins likely confer a benefit independent of their lipid-lowering capabilities.

Oral N-acetylcysteine is no longer recommended for renoprotection prior to cardiac catheterization. Given the lack of benefit observed across a number of trials, the administration of N-acetylcysteine is no longer recommended for the purposes of preventing contrast-induced acute kidney injury. Adequate hydration remains the only Class I recommendation in the 2011 guidelines, although no specific fluid type is mentioned (i.e., normal saline vs. sodium bicarbonate).



We were fortunate to have the opportunity to meet with our interventional cardiologists earlier this week, where we discussed several of these updated recommendations and how best to implement them at our institution. Processes for updating our order sets and standards of practice are already underway.


References

1. 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.
2. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86.
3. Mahaffey KW, Wojdyla DM, Wallentin L, et al; PLATO Investigators. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2011 Aug 2;124(5):544-54.
4. Mehta SR, Tanguay JF, Yusuf S, et al; CURRENT-OASIS 7 trial investigators. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010 Oct 9;376(9748):1233-43.
5. Kastrati A, Neumann FJ, Mehilli J, et al; 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.
6. Briguori C, Visconti G, Colombo A, et al. Novel approaches for preventing or limiting events (Naples) II trial: impact of a single high loading dose of atorvastatin on periprocedural myocardial infarction. J Am Coll Cardiol. 2009 Dec 1;54(23):2157-63.

AIM-HIGH - Wrong weapon, wrong target, or both?

Ever since the news broke earlier this year that the National Heart, Lung, and Blood Institute (NHLBI) would be terminating the AIM-HIGH trial of extended-release niacin early due to lack of efficacy,  clinicians have been eagerly awaiting release of the full results.  Following their publication last week in conjunction with the 2011 American Heart Association meeting in Orlando, FL, the results of AIM-HIGH [1] have been the subject of intense controversy.

Although statins have been shown to reduce the risks associated with coronary artery disease, some residual risk remains even in patients who achieve target concentrations of low-density lipoprotein (LDL).  Some of this risk has been attributed to low concentrations of high-density lipoprotein (HDL), which have been shown in epidemiologic studies to be an independent predictor of cardiovascular risk.  As a result, strategies shown to improve HDL concentrations, such as the use of niacin, have recently garnered significant attention.  The purpose of AIM-HIGH was to evaluate whether the addition of extended-release niacin (Niaspan^®) to intensive statin therapy (i.e., targeting LDL concentrations of 40-80 mg/dL) would further reduce cardiovascular events.

However, the study was terminated 18 months early when a data and safety monitoring board found that the threshold for inefficacy had been met and a small (but not statistically significant) increase in ischemic strokes was observed in the group randomized to niacin therapy.  The decision to terminate the trial early, as well as the conclusions reached by the trial investigators, have been fiercely contested ever since.

The most frequently cited criticism of the trial is that it was stopped far too early to demonstrate the 25% expected reduction in outcomes upon which the trial's statistical power was based.  Some have contended that such differences would require a decade or more to become statistically significant.  Other factors that may have impacted the study's power to detect a difference have also been the subject of debate, including the dropout rate (which exceeded 25% in the niacin group), the increase in HDL observed in the placebo group (which resulted in a net difference in HDL at three years of only 5 mg/dL between the two groups). Other criticisms include the use of small doses (< 50 mg) of niacin in the placebo group (i.e., to induce the common "flushing" effect that would have otherwise unblinded patients randomized to the niacin group) and differences in the dose-adjustments of simvastatin necessary to maintain target lipoprotein levels.

In summary, more questions than answers have emerged out of the publication of AIM-HIGH.  I also awaited the full results to see how it might influence my practice, as we use a fair amount of niacin at our institution.  In short, it probably won't have too much of an impact... for two reasons.

First, I have not routinely recommended the addition of niacin solely for the purpose of improving HDL.  In the vast majority of cases, there are clinical reasons that preclude its use (e.g., the patient is far from achieving a target LDL concentration) or there are more compelling patient-specific strategies for improving HDL (e.g., dietary modification, increased physical activity, moderation of alcohol intake, smoking cessation) rather than adding yet another drug. Where I have found myself recommending niacin is in patients without diabetes (or in whom hyperglycemia is well-controlled) who, despite having LDL concentrations at goal, have significantly elevated triglycerides (> 200 g/dL).  Triglycerides carry significant atherogenic risk and elevated concentrations have been shown to be an independent predictor of heart disease [2]; therefore, in patients with LDL concentrations at goal and in whom other risk factors are well-controlled, the addition of niacin to target isolated triglyceride elevations still seems reasonable.

The second reason why I have not recommended the use of niacin for improving HDL concentrations is that I am not convinced that targeting HDL with pharmacologic strategies (niacin or otherwise) is associated with compelling improvements in outcomes. From what limited data does exist, the exact role of HDL appears far more complex than we initially thought, making strategies for targeting it less intuitive than the management of other dyslipidemias.  However, ongoing focus has been placed on strategies to impact HDL, including the use of cholesteryl ester transfer protein (CETP) inhibitors (e.g., evacetrapib) and HDL infusions, both of which are still too early in studies to demonstrate significant results. There is still a part of me that believes HDL may not be as simple a surrogate marker to target as LDL -- instead, it may be a more global marker of atherogenic risk and perhaps our efforts would be better spent emphasizing those non-pharmacologic strategies known to improve HDL (e.g., physical activity, smoking cessation) but are also associated with independent benefits in reducing cardiovascular risk.

Critics of AIM-HIGH now await the results of HPS2-THRIVE, which recently completed patient enrollment and pairs niacin with laropiprant, a prostaglandin D antagonist that reduces the problematic cutaneous effects associated with niacin therapy. In the meantime, the two lessons I have taken away from AIM-HIGH are 1) statins remain the most proven strategy for impacting cardiovascular risk and should always be attempted first; and 2) no pharmacologic strategy targeting HDL in patients with LDL concentrations at goal has yet to be associated with overall improvements in cardiovascular risk.

References

1. The AIM-HIGH Investigators. Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med. 2011 Nov 15.
2. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998;81:7B-12B. 

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.