Results tagged “statins” from Pathophilia

Although the primary endpoint was not achieved in a recent phase 2 study, high-dose atorvastatin (Lipitor; Pfizer), like the interferon betas, may reduce the likelihood of full-blown multiple sclerosis after a first attack.*

The results of the placebo-controlled trial (N = 81), which were reported last week at the annual meeting of the American Academy of Neurology in Toronto, showed that atorvastatin 80 mg/d significantly reduced the odds of new T2 lesions on brain MR images at 12 months. However, the percentages of patients developing 3 or more new T2 lesions or 1 or more clinical relapses (the combined primary endpoint) were not significantly different between atorvastatin and placebo treatment (49% vs 56%; P = .65).** And while the odds of remaining free of active (ie, gadolinium-enhancing) MR lesions were higher with atorvastatin, this finding also did not reach statistical significance.

The study was originally designed to enroll 150 patients; however, because of slow recruitment, it was stopped after treatments were randomized to 81 patients. The study was sponsored by the NIAID and managed by the Immune Tolerance Network, which receives support from Pfizer and Biogen Idec.

The rationale for assessing atorvastatin in MS relates to its ability to modulate immune reactions and reverse disease in rodent models (ie, experimental autoimmune encephalomyelitis). Open-label studies also suggested clinical benefit with atorvastatin in relapsing-remitting MS.

At MedPage Today, the lead investigator, UCSF's Emmanuelle Waubant, indicated that the results are hypothesis generating—meaning that they warrant phase 3 study.

* AKA clinically isolated syndrome (CIS) manifesting, for example, as optic neuritis, spinal cord syndrome, or brainstem dysfunction.

** Those patients who experienced the primary endpoint were offered weekly IM interferon beta (Avonex; Biogen Idec).

T2-weighted supraventricular horizontal MR image from Harvard's Whole Brain Atlas. Multiple subcortical MS lesions are evident, including a very prominent lesion in the patient's right (left to the viewer) frontal area. The web site also offers a very cool time-lapsed movie of developing MS lesions.

Today: Addressing Friday's semi-interesting news while ignoring yesterday's monumental news.

Last week, the FDA released its warning about an increased risk of myopathy with high-dose simvastatin (Zocor; Merck). The warning is based on a review of preliminary safety data from the SEARCH trial and "other sources." The data show that, while the risk of myopathy is considerably higher with high-dose simvastatin (vs low-dose simvastatin), it is still relatively uncommon (<1%).

Risk	Simvastatin 80 mg/d (n = 6031)	Simvastatin 20 mg/d (n = 6033)
Myopathy	52 (0.9%)	1 (0.02%)
Rhabdomyolysis*	11 (0.02%)	0

The agency also reemphasized several warnings about the heightened risk of myopathy with simvastatin specifically and statins (or HMG CoA reductase inhibitors) generally. These warnings include the use of concomitant drugs that inhibit the CYP3A4 enzyme and thereby increase the concentrations of some statins—namely atorvastatin (Lipitor; Pfizer), lovastatin (Mevacor; Merck), and simvastatin.

In fact, statins have been recognized to increase with risk of myopathy and rhabdo (typically in a dose-dependent fashion) since the Dawn of Statins in the mid-1980s (beginning with Mevacor).** Yet, despite more than 20 years of clinical experience with statins (and squillions of dispensed prescriptions), we still don't know exactly how statins can cause myopathy.

The mystery necessitates a shortish, painful trip down Biochemistry Lane.

According to a literature review (see, for instance, here), the leading hypothesis implicates the statin-induced depletion of isoprenylated proteins that are products of the cholesterol-producing HMG CoA-reductase pathway. Depletion of these isoprenylated proteins, or isoprenoids, may lead to high levels of calcium in muscle cells, which activate mitochondria-triggered apotosis.

Now: Must read People magazine.

SEARCH = Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine.

* Muscle breakdown with high creatine kinase (CK) levels (generally 10 or more times the upper limit of normal). The big risk with rhabdomyolosis is myoglobin-induced renal failure.

** Bayer's cerivastatin (Baycol) was famously recalled from the worldwide market in 2001 owing to an increased risk of rhabdomyolysis (especially when compared with other marketed statins). According to Law and Rudnicka, the incidence of statin-induced rhabdo (excluding Baycol-induced rhabdo), is 3.4 per 100,000 person-years of treatment; the fatality rate of rhabdo is about 10%.

Image of right quadriceps muscles from Gray's Anatomy (1918).

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.

Another study, published in the latest issue of Neurology, supports the use of statin therapy* after a first-time ischemic stroke to reduce the risk of recurrent stroke. Moreover, data support the use of post-stroke statin therapy to reduce the risk of long-term mortality.

In a retrospective, observational study of the Athenian Stroke Registry (N = 794), the risk of a second stroke was reduced by 46% (absolute risk reduction, 16.3% - 7.6% = 8.8%; P = .002) with statin therapy during a 10-year period.** The risk of death during follow-up was also significantly reduced with the use of post-stroke statins: 11 deaths among statin-treated patients vs 213 among non-statin-treated patients. These data remained consistent after adjustments were made for blood-pressure control and 12-month lipid levels—suggesting that statin-related neuroprotection is achieved independently of lipid control. (Other independent predictors of mortality after a first-time stroke included a history of coronary and peripheral artery disease, atrial fibrillation, heart failure, and stroke severity.)

In most cases, statin therapy was continued after the first stroke; although some patients initiated statin therapy after their first stroke. Medication adherence rates were estimated at about 70%. Subanalyses of data on the basis of statin type or dosage were not performed owing to their limited statistical power.

Approximately 30% of the 700,000 strokes that occur each year in Americans are recurrent strokes.

* Simvastatin 10-40 mg/d (34%); atorvastatin 10-40 mg/d (26%); pravastatin 20-40 mg/d (22%); or fluvastatin 40-80 mg/d (18%).

** There was no significant difference in the time of second stroke in the 2 treatment groups: 21 vs 19 months.

CT brain image showing massive right hemispheric infarct with midline shift; from Wikipedia.

Here's the impression: As much as Steven Nissen, head of cardiology at the Cleveland Clinic, hates the cholesterol-lowering combo pill Vytorin (ezetemibe/simvastatin; Merck/Schering-Plough), he adores the statin Crestor (rosuvastatin), or its maker AstraZeneca, or both. The evidence is in a string of loving quotes from Nissen in the lay press about the positive results of the company's JUPITER study, which were concurrently presented at the ongoing Scientific Sessions of the AHA and published in the latest issue of the NEJM.

Nissen tells Bloomberg, "This may be the most important trial we've seen in a decade," and that the study findings are an "out-of-the-park home run."

He tells the LA Times, "It's a blockbuster. It's absolutely paradigm shifting."

He tells CNN, "This is a huge reduction, unprecedented reduction in risk occurring very quickly."

He tells Forbes, "It's potentially a game-changer."

He tells Time, "This is unprecedented...I have never seen a result of this magnitude reduction in risk. The results were significant enough to stop the study 3 years early."

He tells The Washington Post, "It's a breakthrough study," and "This changes medical practice in a major way. People are going to flock to their doctors to get their [c-reactive protein] measured and if it's elevated, they will say, 'Here, this drug you can take.' We'll save many lives and a lot of money."

He tells USA Today, "This is going to have huge repercussions. It means that men over 50 and women over 60 are going to get their [c-reactive protein] checked, and if they're high, they're going to get 20 milligrams of rosuvastatin...We know that we can reduce their risk of heart attack and stroke and angioplasty by nearly 50%. We've never seen this magnitude of risk reduction in a statin trial."

What's got Nissen (who was not a part of the JUPITER study, but who has received research support from AstraZeneca) so buzzed is that rosuvastatin 20 mg daily, when compared with placebo, reduced the relative risk of the primary endpoint, a first major cardiovascular event,* by nearly 50% in more than 17,000 men or women with nonelevated LDL levels but with high c-reactive protein (CRP) levels. The median follow-up of the study was 1.9 years, and the trial was stopped early because of the favorable results.

But despite the high relative risk reductions observed in the JUPITER study, absolute risk reductions were small:

• Rate of primary endpoint: rosuvastatin, 1.6%; placebo, 2.8% → difference, 1.2%.
• Rate of fatal or nonfatal MI: rosuvastatin, 0.35%; placebo, 0.76% → difference, 0.41%.
• Rate of fatal or nonfatal stroke: rosuvastatin, 0.37%; placebo, 0.72% → difference, 0.35%.

Patients who received rosuvastatin also demonstrated a significantly higher rate of physician-reported diabetes (but not myopathy or cancer): rosuvastatin, 3.0%; placebo, 2.4% → difference, 0.6%. Nissen's evidently nowhere near as worried about this adverse event (which undoubtedly raises CV risk) as he was about the possibly fluky cancer risk in the SEAS trial of Vytorin.  

The rationale for the JUPITER study is based on the proposed CV risk associated with high levels of CRP, an inflammatory biomarker and a proposed, independent predictor of vascular events. The lead author of the study, Paul Ridker, is coinventor of a patent (USP no. 7,030,152, along with Charles Hennekens) that describes the use of CRP to evaluate the risk of CV disease.

Other cardiologists, quoted in the press, are more cautious than Nissen about the JUPITER study results and the utility of measuring CRP.

Lori Mosca of Columbia tells Bloomberg, "This finding is clearly expanding the universe of who should receive cholesterol pills, but we need to carefully evaluate at what point it becomes cost-effective to treat the majority of people."

In an NEJM editorial, Mark Hlatky of Stanford writes, "Long-term safety is clearly important in considering committing low-risk subjects without clinical disease to 20 years or more of drug treatment," and adds that the daily cost of rosuvastatin, $3.45, is much higher than that of generic statins.

To this last point, others, like Northwestern's Robert Bonow and Public Citizen's Sidney Wolfe, believe that the JUPITER results can probably be generalized to all statins, including generic versions. AHA president Tim Gardner agrees: "This is a win for all statins," he tells the LA Times and predicts that the findings will be incorporated into practice guidelines.

Of course, the use of a statin in this context depends on the CRP level, which has a checkered history in clinical practice. "When the first [CRP] studies came out," ACC president Douglas Weaver tells Time, "a lot of us measured CRP. Then it fell out of vogue because there was nothing we could do with the result." Scott Grundy of Southwestern advises the New York Times, "CRP is not a standard test that everyone should have," and Daniel Rader of the University of Pennsylvania tells the paper, "It is an additional test that you should do if you're on the fence." Online sources (example) indicate that the cost of high-sensitivity CRP testing is approximately $50.

However, Nissen's (and AstraZeneca's) biggest buzzkill may be found in form of Sanjay Kaul from Cedars-Sinai, who tells Forbes, "I'm convinced CRP is a fad. Maybe there will be a little blip in its use, but many physicians have given up on CRP."

11/10/08 afternoon addendum: Polling results at the NEJM indicate an approximate 50-50 split among responders about whether the JUPITER results should change 1) the approach to laboratory screening and 2) the therapeutic use of statins.

* Nonfatal MI, nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or confirmed death from CV causes.

ACC = American College of Cardiology; AHA = American Heart Association; CV = cardiovascular; JUPITER = Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis.

2006 photo of Steven Nissen testifying at the Hearing on Building a 21st Century FDA.

With the media fixation on the cholesterol-lowering combo Vytorin (ezetimibe/simvastatin)—namely, the negative results of the ENHANCE study and the SEAS trial—it's easy to forget that statins alone have their drawbacks. Case in point is the well-known risk of myopathy with the drug class, which is reported to occur approximately once per 10,000 patients who take lower-dose therapy.

This incidence rate may seem inconsequential, until you remember that about 13 million Americans take statins—some at high dosages and with drugs that can inhibit statin metabolism (thereby increasing the risk of drug-associated myopathy).

In this week's issue of the NEJM, UK investigators report a "single strong association" of simvastatin-related myopathy* with the presence of the rs436657 single-nucleotide polymorphism (SNP) on the gene SLCO1B1 (chromosome 12). The SLCO1B1 gene encodes for an organic anion-transporting polypeptide that has been shown to regulate the hepatic uptake of statins—suggesting that the SNP dictates a class effect for the risk of myopathy. The odds ratio for myopathy was 16.9 (95% CI: 4.7, 61.1) in individuals homozygous for the C (cytosine) allele, versus individuals homozygous for the T (thymidine) allele.

Genetic data were collected and analyzed from 85 subjects who developed myopathy while taking simvastatin 80 mg/d in the Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) (N = 12,064) and compared with data from 90 subjects who did not develop myopathy while taking high-dose simvastatin. The SNP association with myopathy in SEARCH was corroborated by data from the Heart Protection Study of simvastatin 40 mg/d; although the relative risk with a C allele was less robust in this lower-dose study.

Other relative risks for baseline patient characteristics from SEARCH reveal a markedly elevated risk of simvastatin-associated myopathy with the concomitant use of amiodarone.

Characteristic	Relative Risk of Definite or Incipient Myopathy During First Year (95% CI)
Age ≥65 vs <65 y	2.3 (1.3, 4.1)
Female vs male	1.6 (0.9, 3.0)
GFR <60 vs ≥60 mL/min/1.73 m2	2.4 (1.3, 4.3)
Creatinine  ≥85 vs <85 µmol/L	2.5 (1.4, 4.6)
Amiodarone use vs no use	8.8 (4.2, 18.4)
Calcium antagonist use vs no use	2.7 (1.6, 4.5)
DM vs no DM	1.2 (0.6, 2.7)

The authors conclude that genotyping of SLCO1B1 polymorphisms may enable safer statin treatment, and Yusuke Nakamura, MD, PhD, advises in an accompanying editorial that SLCO1B1 variants must be tested for an association with a more severe myopathic event, statin-induced rhabomyolosis, as soon as possible.

* Reversible.

The fact can never be emphasized sufficiently: The results of retrospective, observational studies do not necessarily predict the outcomes of prospective trials.

Case in point is the missed primary endpoint in the prospective, placebo-controlled SEAS trial, in which the combination of ezetimibe and simvastatin (Vytorin; Schering-Plough/Merck) failed to reduce major cardiovascular events associated with aortic valve or atherosclerotic disease. These results follow those of 2 double-blind, placebo-controlled studies of atorvastatin (Lipitor; Pfizer) in aortic stenosis (AS) (see here and here), which also showed that the cholesterol-lowering drug did not alter AS progression.

The proposal that statins may alter the course of AS isn't a bad one, given the association between hypercholesterolemia, coronary artery disease, and atheroma. And in fact, several retrospective, observational studies showed that statin therapy delayed AS progression, as measured by hemodynamics and valvular calcification. But the idea, clearly, has not been realized to date in prospective evaluations.*

Two other interesting results of the SEAS trial, according to the press release, are 1) a significant reduction of the secondary endpoint of atherosclerotic events (nonfatal MI, CABG, PCI, hospitalization for unstable angina, nonhemorrhagic stroke, and cardiovascular death); and 2) a significant and unexplained increase in the incidence of cancer (9.9% vs 7.0%; P = .02).

The former result may portend a positive outcome in IMPROVE-IT, a comparison of ezetimibe/simvastatin with simvastatin alone to reduce the primary composite endpoint of major coronary events, stroke, or cardiovascular death. As far as a potential cancer risk is concerned, an independent analysis of the data from IMPROVE-IT and another ezetimibe/simvastatin study, SHARP, revealed that the overall risk of cancer is not increased with the drug.

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

* A prospective study of rosuvastatin in AS is ongoing. Results are expected at the end of the year.

Update: Over at the Disease Management Care Blog, Jaan Sidorov considers the blogger-fomented Vytorin-cancer scare and says, more or less, "Drink your juice, Shelby."