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Another Winter Solstice, another anniversary for the Pathophilia blog. Today marks 2 years of up-and-running blog time, which is 3½ years in Hollywood-marriage time.

And because anniversaries and a closing year prompt reflection, here are Pathophilia's top 10 stories for the year in medicine, pharma, and film noir on DVD. (Ho-ho-ho! So rare that I get to use the blog's strikeout feature as lame joke.)

No. 10: More Dumping on Merck's Vytorin, Zetia

The year began with continued debate (to put it nicely) about how to assess emerging cancer data from clinical trials of the anti-cholesterol combo drug Vytorin (ezetimibe/simvastatin; Merck). (For lots of necessary background, start at last year's No. 6 story.)

In a Smackdown: New England-Style, prominent cardiologist Steven Nissen essentially charged Sir Richard Peto and his colleagues with unethical behavior, when they separately analyzed cancer data from the SEAS trial (which suggested an increased drug-related cancer risk) and data from the ongoing SHARP and IMPROVE-IT studies (which did not). Nissen believed that data from all 3 studies should have been combined for the analysis (which would have affirmed a cancer risk); but Peto, a statistician and epidemiologist, stressed the importance of separating data in a hypothesis-generating study (eg, the SEAS trial) from data in hypothesis-testing studies (eg, SHARP and IMPROVE-IT). His analysis did not indicate an increased cancer risk with the drug.

At the same time, the FDA attempted to quell some of the anti-Vytorin sentiment and downright company-directed schadenfreude caused by the delayed results of 2008's troubled ENHANCE study. (And if you still don't know what the ENHANCE study is, go back to last year's No. 6 story.) The agency emphasized the importance of lowering the LDL cholesterol level (which Vytorin does) to reduce cardiac risks, like MI. The FDA also weighed in on why the ENHANCE study did not show a reduction of another surrogate marker for vascular disease, CIMT, with the addition of ezetimibe to simvastatin. Speculation included the selectiveness of the study population.

Months later, an Abbott-sponsored phase 4 trial (ARBITER 6-HALTS), which pitted the company's Niaspan (extended-release niacin) against Zetia (the ezetimibe half of Vytorin) was terminated early—and not because of safety concerns. The Street speculated that Abbott's drug had outperformed Zetia in the open-label study of high-risk adults. The Street was right.  

At the Scientific Sessions of the American Heart Association in November, results of ARBITER 6-HALTS showed that Niaspan outperformed Zetia in 5 of 7 outcomes, including a composite clinical outcome. Many media reports played up Niaspan's effects on CIMT at the expense of Zetia, while downplaying tolerability issues (eg, flushing) and the fact that the study population was small (N = 208) and selective: enrollees were statin-treated adults who had already attained target LDL levels (<100 mg/dL) and had moderately low HDL levels. Niaspan in such patients would be expected to elevate HDL, and Zetia would be expected to further lower total cholesterol and LDL levels—which is what the investigators found.

Relatively minimal attention was given to another small placebo-controlled study of extended-release niacin, also presented at the AHA sessions, in which changes in carotid-wall plaque (via MRI) were comparable in the 2 treatment groups.

Merck's Zetia/Vytorin-related troubles, vis-a-vis 2-plus years of media coverage, were epitomized in an end-of-year article by Forbes reporter Matthew Herper—who showed his continued disdain for the drugs and their marketing in a less-than-objective synopsis of results from relevant clinical trials.

Herper and others like him have 2 more years to capitalize on the controversies surrounding Zetia and Vytorin. At that time, results of the long-running IMPROVE-IT study, in which Vytorin is compared with simvastatin monotherapy in at-risk adults, will be available. The primary and major secondary endpoints in this study aren't surrogate markers, like LDL and CIMT, but actual clinical events. 

ARBITER 6-HALTS = ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis; CIMT = carotid intima-media thickness; ENHANCE = Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia; HDL = high-density lipoprotein; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis; SHARP = Study of Heart and Renal Protection.

Public-domain image of Hamilton-Burr duel, which admittedly took place in New Jersey (not New England), from Wikipedia.

12/22/09 update: The FDA says it's "unlikely" that Vytorin and Zetia increase the risk of cancer; although the agency can't rule out the possibility, according to today's WSJ. The agency's announcement comes after its own review of cancer data from the SEAS trial.

Never missing an opportunity to engage in a Zetia (aka ezetimibe) pile-on, Forbes reporter Matthew Herper shows his continued disdain for the drug and its marketing in his most lopsided article yet. Herper's less-than-objective synopsis of Merck's Zetia-related troubles follows results of a recent, small head-to-head study, in which Abbott's Niaspan (extended-release niacin) outperformed Zetia in a highly selected population.

The essential problem with Herper's (and others') coverage of Zetia: He fails to stress that the drug significantly lowers LDL cholesterol—a well-recognized risk factor for vascular disease and a primary target of prevention guidelines. Herper is correct in writing, "No trials show that [Zetia] prevents heart attacks"; but he neglects to remind his readers that, at one time, the same could have been said of Pfizer's blockbuster statin Lipitor (atorvastatin).

Lipitor came to market in 1996 because it significantly lowered LDL-C; but Lipitor had not yet been shown to prevent clinical vascular events like other statins. Nevertheless, Lipitor quickly became the number-one statin because 1) it reduced LDL-C by a relatively greater percentage than other statins and 2) clinicians believe that the LDL-C level is directly related to the risk of vascular events. Lipitor wasn't approved to reduce the risk of vascular events until 2004.

Herper claims, "Merck's clever marketers have spun straw into gold"—a metaphor that wrongly equates the lowering of the LDL-C level with worthless "straw." To support his claim, he cites results of the Niaspan study and the infamous ENHANCE study, both of which enrolled highly selective at-risk populations and used another surrogate marker for vascular disease—the ultrasound measurement of carotid intima media thickness (CIMT). Merck (and Schering-Plough) reportedly struggled with the quality of the CIMT measurements in the ENHANCE study, and some investigators have questioned the usefulness of CIMT generally to assess cholesterol-lowering drugs. For instance, in the placebo-controlled CASHMERE trial, Lipitor failed to significantly alter CIMT in postmenopausal women, despite that fact that the statin undeniably reduces the risk of cardiac events and stroke.

Herper adds Zetia-disparaging quotes from prominent cardiologists, like Sanjay Kaul (who described Zetia as "the miracle of marketing, not the miracle of medicine") and renowned Zetia/Vytorin basher Steve Nissen ("We've spent billions on a drug that may turn out to be a placebo.") Herper also implicitly chastises Merck for waiting 3 years after Zetia approval (in 2002) to begin the IMPROVE-IT study, in which Vytorin (the combination of ezetimibe and simvastatin) is being compared with simvastatin alone to reduce the risk of a composite vascular outcome. Vytorin was FDA approved in 2004.

Herper also unfairly casts aspersions at prominent cardiologists Michael H. Davidson and Antonio M. Gotto, Jr, for providing "lecture and consulting" services to Merck after the results of the ENHANCE study became public. Herper implies that these physicians were paid off to promote the drug, despite the fact that the small and troubled ENHANCE study failed to show the benefit of adding Zetia to statin therapy in a highly select group of patients (ie, individuals with familial hypercholesterolemia). Herper's information was evidently supplied by the office of Senator Grassley, ranking minority member of the Senate Finance Committee.

A quick examination of the medical literature reveals that both physicians (like so many others) endorse the vascular benefits of lowering the LDL-C level. For instance, in a recent editorial, Gotto writes, "Lowering elevated [LDL-C] is a surefire way to reduce cardiovascular risk." But he also acknowledges the potential drawbacks of using surrogate markers to assess the protective benefits of drugs by adding, "As monotherapy, [Zetia] at 10 mg reduces LDL-C by approximately 17%, but when added to any dose of statin, it reduces LDL-C by an additional 25%. Given the well-established log-linear relationship between LDL-C and relative risk for [coronary heart disease], these greater degrees of LDL-C reduction can be expected to result in improved clinical outcomes, although this has not yet been proven in the case of ezetimibe."

In another editorial ("Is LDL-C passed its prime?"), Davidson more clearly lays out the shortcomings of applying general guidelines to what is probably a very heterogenous at-risk population. He notes that the rising number of patients with metabolic syndrome and those currently taking statins present more complex portraits of dyslipidemia and its associated vascular risks. He argues that, in these subgroups, other lipid markers—like apoB, LDL-particle number, and non-HDL levels—become relatively more predictive of coronary heart disease. Consequently drugs that specifically affect these levels (for example, niacin) may be more protective in these specific populations.

CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein.

Niacin, the B vitamin, may only provide protective benefits in a select group of patients with atherosclerotic vascular disease. This conclusion is based on the somewhat conflicting results of 2 studies, both of which were presented at the ongoing Scientific Sessions of the American Heart Association.

In a highly anticipated, Abbott-sponsored phase 4 trial (abbreviated ARBITER 6-HALTS), extended-release niacin (Niaspan) outperformed Merck's ezetimibe (Zetia) in 5 of 7 outcomes, including a composite clinical outcome. But the small study population (N = 208) was a selective one, in which high-risk statin-treated adults had already attained target LDL levels (<100 mg/dL) and had moderately low HDL levels. Niacin therapy in such patients would be expected to elevate HDL, and ezetimibe treatment would be expected to further lower total cholesterol and LDL levels—which is what the investigators found.

Change in Outcome*	Extended-Release Niacin 2000 mg/d (n = 97)	Ezetimibe 10 mg/d (n = 111)	Statistical Significance
Mean CIMT, mm (primary outcome)	–0.0142 ± 0.0041	-0.0007 ± 0.0035	P = .01
Mean CIMT at 8 months, mm	–0.0102 ± 0.0030	+0.0014 ± 0.0020	P = .001
LDL, mg/dL	–10.0 ± 24.5	–17.6 ± 20.1	P = .01
HDL, mg/dL	+7.5 ± 9.2	–2.8 ± 5.7	P < .001
Cholesterol, mg/dL	–6.9	–18.8	P = .025
Triglycerides, mg/dL	–36	–9	P = .018
Major CV events	2/160	9/165	P = .04
Adverse events leading to study withdrawal	17/27	3/9	P = .12
Adherence to study medication, %	88 ± 15	95 ± 8	P = .001

In another small study (Abstract 685), this time of 145 statin-treated elderly patients in the Baltimore area, extended-release niacin (1500 mg/d) significantly lowered LDL and raised HDL at 18 months, when compared with placebo. But declines in carotid-wall plaque (as measured by MRI) were comparable in the 2 treatment groups. The investigators concluded that the addition of niacin to statin therapy did not provide "further benefit," despite the lipid panel changes.

The hurdle with using and maintaining high-dose niacin therapy is tolerability of the drug. In ARBITER 6-HALTS, 36% of niacin-treated patients experienced flushing, and adherence to study medication was significantly lower.

According to the Niaspan package insert, therapy must be initiated at 500 mg and given at bedtime to reduce the incidence and severity of side effects. The dosage should not be increased by more than 500 mg in any 4-week period. (Consequently the dosage used in ARBITER 6-HALTS could be attained in 3 months or more.) The most common side effects with Niaspan treatment are flushing, diarrhea, nausea, vomiting, increased cough, and pruritus. 

ARBITER 6-HALTS = ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

N.B.--ARBITER 6-HALTS was terminated early, in June, and stock analysts speculated that the findings favored the addition of niacin to statin monotherapy.

* ARBITER 6-HALTS outcomes were assessed at 14 months, unless otherwise indicated.

News source: HealthDay.

Image of niacin structure from Wikipedia.

A novel antiplatelet drug, ticagrelor, from AstraZeneca delivered a knockout punch to uber-drug clopidogrel (Plavix; BMS/sanofi-aventis) in a phase 3 study of patients with acute coronary syndrome (ACS). Results of the head-to-head trial were presented Sunday at the ongoing congress of the European Society of Cardiology (ESC) in Barcelona. Trial specifics were simultaneously published online in The New England Journal of Medicine.

Both ticagrelor, trade named Brilinta [oy], and clopidogrel belong to the thienopyridine class of oral antiplatelet agents; although ticagrelor, unlike clopidogrel, is a reversible inhibitor of the P2Y12 receptor on platelets. (Read on for the importance of this distinction.)

The international AZ-sponsored trial, abbreviated PLATO, enrolled 18,624 patients with ACS* who received randomly assigned ticagrelor (180-mg loading dose followed by 90 mg bid) or clopidogrel (300-600-mg loading dose followed by 75 mg qd). (Before randomization, the overwhelming majority patients had received aspirin, and about half had received clopidogrel. During the trial, everybody got aspirin, 75-100 mg/d.) The average treatment time was 278 days (range, 6-12 months), and the follow-up rate was phenomenal—better than the purity of Ivory soap: 99.97%.

Rates of the composite primary endpoint—MI, stroke, or cardiovascular death—were 9.8% with ticagrelor and 11.7% with clopidogrel. The outcome amounts to a statistically significant relative-risk reduction of 16% with ticagrelor. Moreover, investigators observed a statistical difference between the 2 drugs at 30 days of treatment. Rate differences for several secondary endpoints, including MI or cardiovascular death, also favored ticagrelor. However, both drugs performed similarly with respect to the isolated outcome of hemorrhagic or ischemic stroke (1.5% vs 1.3%).

The ho-hum stroke outcome may have something to do with the relatively reduced risk of stroke in patients with ACS (vs the stroke risk in patients with a history of stroke). There is also the possibility that some thienopyridines aren't particularly great at preventing stroke, at least in some patients.** For instance, in the mammoth pivotal trial for clopidogrel (published way back in 1996), the drug edged out aspirin with respect to the composite outcome of ischemic stroke, MI, or vascular death in at-risk patients; however, clopidogrel was no better than aspirin in the post-hoc analysis of a stroke-only outcome. Most of the overall protective benefit of clopidogrel in this study was observed in patients with peripheral arterial disease. (Although clopidogrel is still recommended as first-line therapy for preventing recurrent stroke.) 

With respect to overall major bleeding, rates with ticagrelor and clopidogrel in the PLATO trial were similar (11.6% and 11.2%). But major bleeding in a non-CABG context was higher with ticagrelor (4.5% vs 3.8%; P = .026). Dyspnea was also more frequent with ticagrelor (14.2% vs 9.2%) and led to the discontinuation of the drug in 1% of treated patients.

In addition to outperforming clopidogrel on efficacy measures, ticagrelor has the advantage of not being a prodrug—meaning that metabolic conversion is not necessary to achieve antiplatelet activity. Consequently ticagrelor is faster acting than clopidogrel. And because ticagrelor is a reversible inhibitor of platelets, its activity wears off more rapidly than that of clopidogrel. This property enables emergent CABG, should the procedure be necessary in ACS patients who don't respond to coronary stenting. (However, rates of major bleeding during CABG were not significantly different between the 2 drugs [7.4% vs 7.9%] in the PLATO trial). The downside of ticagrelor is its twice-a-day administration. 

In the United States, clopidogrel goes off patent in 2011 (according to the LA Times); there's also a recent history of several foreign generics encroaching the market.

CABG = coronary-artery bypass grafting; PLATO = PLATelet inhibition and patient Outcomes.

* With ST-segment elevation intended for primary percutaneous coronary intervention (PCI) or without ST-segment elevation intended for invasive or medical management.

** Very recent data indicate that clopidogrel's activity is reduced in patients who are poor metabolizers of the drug (ie, those patients with genetically reduced function of CYP2C19, a P450 component). The genetic variant is associated with the reduced inhibition of platelet aggregation and an increased risk of cardiovascular events or death. About 30% of the population have the CYP2C19 variant.

According to yesterday's WSJ, stock analysts are speculating that Abbott's extended-release niacin (Niaspan) outperformed ezetimibe (Zetia; Merck/Schering-Plough) in a phase 4 head-to-head atherosclerosis study that was terminated early in June. The NIH clinical-trials web site indicates that an independent steering committee stopped the trial on the basis of results from a prespecified, blinded interim analysis and adds that the study was not stopped because of safety concerns.

The principal investigators are otherwise mum, advising that the trial results will be presented in mid-November at the Scientific Sessions of the American Heart Association. But the logical conclusion is that one drug significantly outperformed the other; stock analysts are placing their bets on Niaspan, possibly because the study is cosponsored by Abbott.*

The randomized, open-label, 2-center study, abbreviated ARBITER 6-HALTS, was designed to compare the effects of raising the HDL level (with Niaspan) with those of lowering the LDL level (with Zetia) at 14 months. The primary endpoint, as in the notorious ENHANCE study, was the mean change in the intima-media thickness of the common carotid artery (CIMT). (Presumably all enrollees received statin therapy; so Niaspan and Zetia were add-on medications.)

It's important to note that the NCEP ATP III guidelines stress the lowering of the LDL level as the primary target of cholesterol-altering therapy. Therefore Abbott has a vested interest (and an uphill battle) in showing that raising the HDL level with Niaspan is just as good as, or possibly better than, lowering the LDL level with Zetia. In a previous, placebo-controlled study, ARBITER 2 (N = 167), Niaspan reduced the rate of CIMT progression when added to statin therapy in high-risk patients who did not have insulin resistance; however, the drug did not appear to alter the risk of cardiovascular events at 1 year.

Unlike ARBITER 6-HALTS, ARBITER 2 was placebo controlled, and study drugs were assigned in a double-blind fashion. A drawback of both trials is the fact that the primary endpoint, the mean change in CIMT, is merely a surrogate marker for clinical cardiovascular outcomes.

ARBITER 6-HALTS = ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NCEP ATP III = Third Adult Treatment Panel of the National Cholesterol Education Program.

* The other cosponsor is the Walter Reed Army Medical Center.

This week, 2 articles examine the possible benefit of closing a patent foramen ovale (PFO), the vestige congenital hole between the left and right atria. Individuals with isolated PFO are typically asymptomatic, but longstanding reason has dictated that PFO, as a conduit for cardiac emboli, increases the risk of stroke and is a prominent cause of brain infarction in young adults. At least 2 studies indicated that the prevalence of PFO is increased (up to 45%) in patients with cryptogenic stroke.

However, a meta-analysis of 4 trials (N = 1081), published in this week's Neurology, indicates that the pooled relative risk (RR) of recurrent ischemic stroke or TIA in patients with PFO (vs those without) is only 1.1 (P = .149). The pooled RR for ischemic stroke alone in patients with PFO is 0.8 (P = .666).* Post-event treatments in these studies included antiplatelet therapy, warfarin, and/or surgical closure (the latter in 28% of patients with PFO), but the authors advise against using their meta-analysis data—which cannot be adjusted for important study differences—to assess therapeutic efficacies.

In this week's JAMA, a second study, performed at the Cleveland Clinic, assessed the effects of closing an incidental PFO—which was seen in 2277 of 13,092 (17%) surgical patients. Surgical closure was performed in 639 patients (28%) with PFO. The investigators calculated similar rates of in-hospital death (3.4% vs 2.6%) and stroke (2.3% vs 2.3%) in matched PFO groups. But patients with a repaired PFO were significantly more likely to experience a longer-term postoperative stroke than patients whose PFO was not repaired (2.8% vs 1.2%; P = .04). Surgical closure was statistically more likely in younger patients, in patients undergoing atrial valve surgery, or in those with a history of stroke or TIA. Long-term survival was not affected by PFO closure.

Currently there are no completed randomized trials comparing medical therapy with surgery in patients with cryptogenic stroke and PFO. The NIH database indicates that at least 1 US-based controlled trial is active but not recruiting.

In 2004, the American Academy of Neurology concluded that PFO does not increase the risk of subsequent stroke or death in medically treated patients. However, the combination of PFO and an atrial septal aneurysm possibly increases the risk of recurrent stroke (but not death) in medically treated patients who are younger than 55 years of age.

TIA = transient ischemic attack.

* In patients with PFO, the pooled absolute rate of recurrent stroke or TIA is 4 events per 100 person-years; the pooled absolute rate of recurrent stroke is 1.6 events per 100 person-years. The authors write that this rate is similar to the annual rate of major bleeding with warfarin therapy for cryptogenic stroke.

Mini-graphic of atrial septal defect (ASD) attributed to the NIH.

At least according to the FDA.

The agency announced yesterday that patients should not stop taking Vytorin (ezetimibe/simvastatin) or any other cholesterol-lowering medication on the sole basis of the ENHANCE trial results. The conclusion follows the FDA's review of the final trial report, in which the combo drug was no better than simvastatin alone for reducing carotid intima-media thickness (CIMT) at 2 years. However, the LDL cholesterol level dropped 56% with Vytorin and 39% with simvastatin alone—a statistically significant difference.

The FDA maintains that an elevated LDL cholesterol level is an important risk factor for cardiovascular disease and that lowering the LDL level reduces that risk. The FDA also speculated as to why a larger reduction of the LDL level with Vytorin was not associated with a significantly reduced CIMT in the ENHANCE trial*:

• Because the ENHANCE population had received prior lipid-altering or statin therapy, subjects demonstrated relatively normal CIMT values at baseline, which made it harder to demonstrate a CIMT difference with Vytorin therapy.
• The duration of the ENHANCE trial, 2 years, was too brief to demonstrate a difference in CIMT with therapy.
• Unknown effects of ezetimibe may negate the beneficial effects of LDL lowering on CIMT.

The FDA advises that the much larger, ongoing IMPROVE-IT study, which pits Vytorin against simvastatin alone and has a primary composite endpoint of cardiovascular events and stroke, should provide more definitive information about the clinical benefits of the drug. The trial, however, won't be completed until 2012.

* The FDA doesn't mention previously reported problems with the CIMT data in the ENHANCE trial, such as missing or biologically implausible data.

ENHANCE = Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein.

So much for looking forward. The new year begins here with leftover business—namely, leftover Vytorin business.

In this year's brand-spanking-new issue of the NEJM, cardiologist and consistent Vytorin critic Steven Nissen officially charges that September's ezetimibe-cancer analysis of Sir Richard Peto et al, in which the authors concluded that the cancer risk with ezetimibe is not increased, "raises disturbing scientific and ethical questions." The Peto analysis was performed in response to a finding in the SEAS trial that ezetimibe, one half of the combo Vytorin pill, may increase the risk of cancer. However, Peto et al found that unblinded adverse-event data from the much larger, ongoing SHARP and IMPROVE-IT studies did not confirm the finding.

Among his criticisms of the Peto analysis, Nissen cites the following in his correspondence:

• The premature unblinding of the ongoing trials, which is "not a reliable approach to the evaluation of drug safety."
• The insufficient exposure to ezetimibe in IMPROVE-IT for assessing drug hazards.
• The failure of Peto et al to report the relative risk of cancer mortality in the 2 studies.
• The limited statistical power of the 2 studies to assess the risk of cancer death with ezetimibe.

Elsewhere Nissen has argued that data from all 3 studies should have been combined to assess cancer risk with the drug.

In their reply, Peto and coauthor Rory Collins stress the importance of separating data in a hypothesis-generating trial—in this case, the SEAS trial—from data in hypothesis-testing studies. They implicitly rationalize the unblinding of cancer data from SHARP and IMPROVE-IT by noting that these are the only large, randomized data sets from which relevant cancer data may be obtained to confirm any increased risk with ezetimibe. They also cite the magnitude of these studies in relation to the SEAS trial; together SHARP and IMPROVE-IT generated 4 times as many cancers as the SEAS trial, but their data did "not suggest any increase in cancer incidence."

Peto and Collins also correct Nissen in his mistaken charge that the authors did not report the relative risk of cancer mortality (and the associated 95% confidence interval) in SHARP and IMPROVE-IT. (The data were right there in the Fig. 4 legend.) Although there were more deaths due to cancer with ezetimibe in the analysis, the difference was not statistically significant (P = .07).

Last, although Nissen did not allege an industry-related conflict of interest by Peto et al (and Nissen's hardly in a position to do so), Peto and Collins, both from the UK, cite their not-so-dispassionate response to the US Congressional Committee on Oversight and Investigations, which raised the issue.

IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis; SHARP = Study of Heart and Renal Protection.

Public-domain image of Hamilton-Burr duel, which admittedly took place in New Jersey (not New England), from Wikipedia.

The comarketers of the cholesterol-lowering combo pill Vytorin (ezetimibe/simvastatin) received a protracted and very public comeuppance in 2008—primarily for delaying the negative and controversial results of a relatively small study of the drug in patients with familial hypercholesterolemia.

Unfortunately for Merck and Schering-Plough, most medical reporters and bloggers viewed the delayed publication of the ENHANCE trial results—which failed to show a reduction in carotid plaque with Vytorin use—as highly suspect. Moreover, the negative results were taken as an indicator of the drug's inability to reduce cardiovascular events in a general at-risk population, and prescriptions plummeted.

The companies' explanation for the delay—namely, that missing or implausible carotid ultrasound data* in the ENHANCE trial had to be accommodated—was viewed as unfair to the trial's principal investigator, John Kastelein. With respect to the trial's clinical implications, little was settled in the professional or public arena when the ENHANCE data were simultaneously presented at the annual meeting of the American College of Cardiology and published in the NEJM in the spring.

In April, Senator Chuck Grassley fired off inquiries to the company CEOs, which instigated a kind of journalistic pile-on from the likes of Matthew Herper at Forbes, Ed Silverman at Pharmalot, and the WSJ Health Blog gang. And the schadenfreude ante was upped when, in September, the industry-sponsored SEAS trial failed to show that Vytorin reduced major cardiovascular events in patients with aortic valve or atherosclerotic disease. To add insult to injury, the data suggested an increased risk of cancer with Vytorin treatment. (However, this latter finding was not supported by a meta-analysis of cancer data from 2 other, ongoing Vytorin studies.)

While the primary endpoint in the ENHANCE trial rests entirely on the validity of the ultrasound measurement of carotid intima-media thickness (CIMT), some investigators question the usefulness of CIMT to assess cholesterol-lowering drugs. In the placebo-controlled CASHMERE trial, Pfizer's Lipitor (atorvastatin) failed to significantly alter CIMT in postmenopausal women, despite that fact that Lipitor undeniably reduces the risk of cardiac events and stroke.

These facts may portend a positive outcome in IMPROVE-IT, a comparison of Vytorin with simvastatin alone to reduce the primary composite endpoint of major coronary events, stroke, or cardiovascular death. However, IMPROVE-IT won't be completed until July 2012.

It is with some embarrassment that an inordinate number of Vytorin posts at this blog were dug up for background reading:

• ENHANCE Study: Basically, the Ultrasound Images Were Crap
• ENHANCE Study: More Much Ado About Suboptimal Data
• ENHANCE Study: Frustration With Trial and Coverage of It
• SP Share Price, Insider Trading, and the ENHANCE Timeline: Now in Fancy Graphs
• ENHANCE E-Mail Exchange: Dear John, John, and...Rick
• ENHANCE Study: The Thing That Wouldn't Leave...the Blogosphere
• Pfizer Attempts to Capitalize on Vytorin's Limited Indications: Oh, the Irony
• Another ENHANCE Panel: Still No Discussion of "Missing" or "Implausible" Data
• Independent Reviewer: ENHANCE Data "Not Acceptable"
• Then and Now: Quality Differences in ENHANCE Data
• Media Retain Big Anti-Jones for ENHANCE, Schering-Plough, and Fred Hassan
• Negative Lipitor Data Raise Doubt About CIMT
• Statins and Aortic Stenosis: Retrospective vs Prospective Study
• Vytorin Is Beaten Up Some More
• Need a Negative Vytorin Quote? Call Dr. Nissen
• Pols Piss Off Peto

* Specifically the carotid intima-media thickness (CIMT).

CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis.

The ill-known procedure of cardiac-death organ donation was raised in the public consciousness by the criminal case of California v. Roozrokh.

On the night of February 3, 2006, a transplant team, including surgeon Hootan Roozrokh, MD, was dispatched by the California Transplant Donor Network to the Sierra Vista Medical Center to harvest the organs of Ruben Navarro, a 25-year-old man with adrenoleukodystrophy and minimal brain function after cardiopulmonary arrest. What happened next is a function of the Rashomon effect, in which the involved medical professionals told differing accounts of a procedure gone wrong.*

What isn't disputed is that Roozrokh took over the end-of-life care of Navarro, in clear violation of general transplant procedures and Sierra Vista policy, and that Navarro didn't die within the required window of time to allow organ harvesting after being withdrawn from life support. An ensuing inquiry into the failed procedure led to an ongoing investigation by the Medical Board of California, civil suits filed by Navarro's mother, and 3 felony counts against Roozrokh: dependent-adult abuse; administering a harmful substance (oral Betadine); and the unlawful prescription of a controlled substance.

At the preliminary hearing in March for Roozrokh's criminal case, the judge dismissed 2 charges against the physician. First, conflicting or vague testimony could not establish that Roozrokh was the physician who administered Betadine to Navarro in the operating room. Second, the judge determined that the unlawful prescription of a controlled substance did not apply in this case, because the relevant California statute exempts drug orders for a patient in a licensed hospital.

At his criminal trial, Roozrokh testified that he stepped in to fill a void in physician care, while others characterized his actions as those of a callous and impatient surgeon, who ordered massive doses of morphine and Ativan (lorazepam) to hasten Navarro's death. Nevertheless, Roozrokh was acquitted of dependent-adult abuse by a 12-person jury last week. Defense attorney M. Gerald Schwartzbach (who successfully defended actor Robert Blake in his murder trial) had contended that his client "could not have violated the standard of care to merit [the charge]...because no such standard applies to the extraordinary circumstances of this case."

Indeed Schwartzbach's statement highlights the absence of a universal protocol for cardiac-death donation at the time of Navarro's death (despite Roozrokh's clear violation of standard transplant procedure). The California Transplant Donor Network did not require physicians or nurses to undergo specific training in cardiac-death donation until 1 year after Navarro's death, and, in fact, the criminal investigation prompted the adoption of training standards for the procedure by the Network. Roozrokh himself had assisted only one such procedure before the night of February 3, 2006.

The use of cardiac death (as opposed to brain death) to obtain organs for transplantation has been accepted practice for more than a decade in the United States, but hospital-based protocols can vary—thereby creating confusion among medical practitioners. In a prepared statement, the jury members in Roozrokh's criminal case expressed their desire for a uniform protocol, reported the San Luis Obispo Tribune:

"Ruben's case had identified that donation by cardiac death is in desperate need" of having a national refined protocol. "Refining the nationwide protocol of DCD organ procurements will be an important part of Ruben's legacy and for that we pay him our respect and owe him our thanks."

In August, ethicist Robert Veatch argued in the NEJM that heart donation after cardiac death raises a logical paradox. He proposed that, if the heart can be restarted in the graft recipient, then the donor could not have been dead in the first place on the basis of cardiac death. Moreover, the very act of removing the "restartable" heart from the donor is equivalent to killing the donor by means of organ removal. Veatch concluded that it is therefore impossible to legally harvest a heart in the setting of cardiac death and wrote that this paradox can only be resolved by either redefining brain death or altering laws to permit heart removal from living donors.

Veatch's argument was printed in the same NEJM issue that included a report of 3 heart transplantations in infants after the cardiac deaths of pediatric donors. 

For more details on the attempted organ donation of Ruben Navarro and a discussion of cardiac-death donation, check out...

• NYT Discovers California (and Roozrokh Case)
• More on Roozrokh Case: Lubarsky Testimony
• Continuing Coverage of Roozrokh Preliminary Hearing: Transplant Expert Testimony
• Roozrokh Prelim Hearing Continues: Conflicting Accounts and Neuro Testimony
• Roozrokh Prelim Hearing: See One, Botch One
• Roozrokh Prelim Hearing: Who Ordered What When?
• Roozrokh Prelim Hearing: Final Testimony
• Surgeon Roozrokh to Face 1 Charge; 2 Dismissed
• The Transplant Paradox: Heart Donation After Cardiac Death
• Transplant Surgeon Acquitted of Dependent-Adult Abuse

Also visit the web site of the San Luis Obispo Tribune for its excellent and complete coverage of the Roozrokh case.  

* Compounding the Rashomon effect in this case is the fact that, during the attempted procedure, no one recorded the administration of medications, and the vital-sign records were lost.