June 15th, 2011
NEJM: FDA Officials Explain the New Simvastatin Label
Larry Husten, PHD
In a perspective published in the New England Journal of Medicine, two FDA officials, Amy Egan and Eric Colman, explain in some detail the recent changes made by the FDA regarding simvastatin. They note that in the SEARCH trial, myopathy developed in 52 (0.9%) patients in the 80-mg group compared with only 1 (0.02%) patient in the 20-mg group. There were 22 cases of rhabdomyolysis with the high dose versus no cases with the low dose. Further, patients at high risk usually developed myopathy early in the course of treatment.
In addition, because simvastatin is “particularly prone to drug-drug interactions,” the risk for myopathy is increased in patients taking high-dose simvastatin who are also taking other drugs, including several commonly used cardiovascular drugs such as amiodarone, diltiazem, and amlodipine.
Finally, the FDA authors summarize data from adverse event reports from all the statins, noting that rates of fatal rhabdomyolysis have been higher with simvastatin 80 mg than with atorvastatin 80 mg or rosuvastatin 40 mg.
The following chart provides a summary of the FDA action:
| Key Components of Recent Safety-Labeling Changes for Simvastatin | |
| 1. Use of the 80-mg dose of simvastatin should be restricted to patients who have been taking it for a long time (e.g., 12 months or more) without signs or symptoms of clinically significant toxic effects on muscle.
2. Patients who are currently taking an 80-mg dose of simvastatin without adverse effects but who need to begin taking an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for a drug–drug interaction. 3. Patients in whom the LDL cholesterol goal cannot be achieved with a 40-mg dose of simvastatin should instead be given other appropriate LDL cholesterol–lowering therapy (e.g., a more potent statin that poses a lower risk of myopathy, such as atorvastatin or rosuvastatin). |
|
| Drug Interactions Associated with Increased Risk of Myopathy and Rhabdomyolysis | |
|
Interacting Agents
Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Gemfibrozil Cyclosporine Danazol |
Prescribing Recommendations
Contraindicated with simvastatin |
|
Amiodarone Verapamil Diltiazem |
Do not exceed 10 mg of simvastatin daily |
|
Amlodipine Ranolazine |
Do not exceed 20 mg of simvastatin daily |
|
Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 qt daily) |
June 15th, 2011
Johnson & Johnson Steps Out of the Stent Market
Larry Husten, PHD
Johnson & Johnson announced today that it is exiting the stent business. The company will discontinue development of its Nevo sirolimus-eluting stent and will end sales of its Cypher family of stents by the end of the year. The company was the manufacturer of both the first stent, the Palmaz-Schatz stent, in the 1990s and the first drug-eluting stent, the Cypher stent, in the early 2000s.
June 14th, 2011
CRT for HF Patients with Moderately Prolonged QRS Interval: Unethical?
Larry Husten, PHD
Approximately 40% of cardiac resynchronization therapy (CRT) devices are implanted in patients with QRS intervals below 150 msecs, but a meta-analysis published in Archives in Internal Medicine finds that these patients may not benefit from the device.
Ilke Sipahi and colleagues performed a meta-analysis that included five CRT clinical trials (COMPANION, CARE-HF, REVERSE, MADIT-CRT, RAFT) with designs that enabled them to examine the effect of QRS duration on outcome. Although patients with severely prolonged QRS had a 40% reduction in risk associated with CRT therapy (CI 0.53-0.67, p<0.001), no benefit at all was observed in the patients with only moderately prolonged QRS. The same finding was observed in patients with class 1 and 2 heart failure as in patients with class 3 and 4 heart failure. The presence or absence of an ICD did not alter the pattern.
The authors point out that between one third and one half of patients who receive CRT don’t benefit from the therapy and then suggest “that a predominant reason for CRT non-response is a suboptimal patient selection criterion for QRS duration.” They recommend an individual patient level analysis of current trials to more precisely identify which patients enjoy the benefits of CRT.
“It may now be unethical…”
In an accompanying commentary, Lynne Warner Stevenson addresses the issue of subgroup analysis, agreeing that skepticism is warranted in trials with negative findings, but asking: “What about those with positive results?” In this instance, she argues, “the results of this meta-analysis are robust enough to anchor a growing suspicion that the patients with QRS in the 120- to 150- millisecond range do not improve after CRT. The trials are remarkably congruent, regardless of clinical class or etiology.” She then writes:
To continue to perform this procedure when benefit is unlikely will undermine enthusiasm for a remarkably effective therapy in appropriate patients. It may have been optimistic to recommend and reward this procedure in patients for whom there was no evidence of benefit; it may now be unethical to recommend and reward this procedure in patients for whom we now have evidence of no benefit.
June 13th, 2011
Increased Mortality Found in MI Patients During Ambulance Diversion
Larry Husten, PHD
MI patients who are diverted to other emergency departments (EDs) while their local EDs are closed have an increased risk for death, according to a new study published in JAMA. Yu-Chu Shen and Renee Hsia analyzed data on all Medicare patients with MI from four California counties who were admitted to the hospital between 2000 and 2005.
At 1 year, the rates of death were:
- nearest ED not on diversion: 29%
- nearest ED <6 hours on diversion on the date of admission: 31%
- nearest ED 6 to < 12 hours on diversion on the date of admission: 30%
- nearest ED 12 or more hours on diversion on the date of admission: 35%
The investigators found several differences of potential importance among the hospitals. For example, the hospitals that received the diverted patients were less likely to have a catheterization laboratory and were more likely to be either a for-profit hospital or a government hospital.
In their conclusion, the authors point out that “diversion is a signal of a larger access problem in the health care system, representing resource constraints that are beyond patient factors and related to the hospital and health care system.” Their results, they write, “suggest that more integrated health care policies from the prehospital to in-hospital setting should include provisions that minimize instances in which hospitals are on diversion for prolonged periods.”
June 12th, 2011
CardioExchange Panel: Whither High-Dose Simvastatin?
CardioExchange Editors, Staff
Last week, the FDA issued a warning high-dose simvastatin because of the risk of myopathy.
CardioExchange got the reactions from a panel we assembled. Whose views do you agree with? What points did our panelists miss?
See a similar panel’s reactions the publication of the SHARP Trial here.
Given the FDA warning, do you see any role for high-dose simvastatin?
I wrote a JAMA editorial about high-dose statins in ACS back in 2004. The FDA should have removed simvastatin 80 mg from the market years ago.
The FDA statement is consistent with a clinically-relevant safety difference that has been recognized for some time now- particularly important among the elderly with reduced renal function and those on certain concomitant therapies. Given numerous safe therapeutic alternatives for high potency statins, I believe simvastatin at the 80 mg/d dose should be avoided. I disagree with the FDA statement from the perspective of whether patients currently taking the 80 mg dose should continue on that dose. I personally favor conversion of any patient taking the 80 mg dose to an alternative treatment approach (different statin or simvastatin dose reduction), to avoid problems from interactions with future concomitant therapies, or changes in the rate of drug clearance.
I stopped using high-dose simvastatin many years ago because of heightened risk of myopathy. I substitute 20-40 mg atorvastatin or 10-20 mg rosuvastatin for patients requiring greater than 40 mg simvastatin. In general, I am not a big fan of initiating high-dose statin therapy, even for patients with ACS. I like to start with low to intermediate statin dose and titrate up to optimize adherence. The adverse event rates related to statins is much higher in the real world practice compared with randomized trials where most patients intolerant to statins are filtered out during the active treatment “run-in” phase prior to randomization.
The concerns have been seen in clinical trials since the A to Z study was published in JAMA in 2004. At least 2 recent reports from the SEARCH study confirmed the risk. Also, simvastatin is cleared by cytochrome P 450 3A4, and many commonly used medications inhibit this pathway, so it is rather easy for patients on this high dose of simvastatin to develop “supra-therapeutic” blood levels of the drug. Of note, attempts at developing the 160 mg dose of simvastatin for clinical use were derailed because of muscle problems.
This is an especially important report because simvastatin is the most commonly used generic statin in the US and its rate of use still is rising. A lot of patients were put on 80 mg of simvastatin when it went generic or are put on it after MIs, and it, quite simply, is not as safe as high dose atorvastatin or rosuvastatin.
June 12th, 2011
CardioExchange Panel: Ezetimibe + Simvastatin for Chronic Kidney Disease — What’s the Point of SHARP?
CardioExchange Editors, Staff
Last week saw the publication of the SHARP trial (Study of Heart and Renal Protection) in which some 9,200 patients with chronic kidney disease (CKD) were randomized to either placebo or the combination of simvastatin and ezetimibe.
CardioExchange put questions about these data to a panel of experts. Whose views do you agree with? What points did our panelists miss?
See a similar panel’s reactions to the FDA warning on high-dose simvastatin here.
Does the SHARP trial tell us anything about the value of adding ezetimibe to statin therapy? And would you derive any recommendations for the treatment of patients with advanced kidney disease from this study?
While ezetimibe was part of the active drug strategy, it is not possible from these data to assess the independent contribution of the drug to the combination strategy. What we did learn is that an LDL lowering strategy with these two drugs in this group of patients is better than placebo. The incremental value of ezetimibe when added to simvastatin (compared with the statin alone) is being tested in the ongoing IMPROVE IT trial. For full disclosure, our research group (DCRI) along with the TIMI study group are leading the IMPROVE IT trial.
SHARP contributes to our clinical decision-making knowledge base given that there was still uncertainty as to the incremental benefit of lipid-lowering therapy in patients with CKD. Lipid-lowering therapy, specifically LDL lowering, in patients with CKD reduces the risk of cardiac events. The magnitude of this effect is consistent with other data in patients without CKD and with comparable levels of LDL lowering. While it is likely, even probable, that the magnitude of LDL lowering is what confers the clinical benefit, the most evidence-based conclusion (and hence the recommendation) is that treatment with this combination in patients with CKD results in a reduction in cardiac events. It’s tempting to state that any strategy that lowers LDL to a similar degree is sufficient to confer the clinical benefit seen in this population, but we can only comment on what was tested in the trial. In addition to the efficacy statement, the combination strategy appeared safe in this population as studied.
This study tells us nothing about the efficacy of adding ezetimibe to stain therapy. It is entirely plausible that the observed benefits were due solely to simvastatin. Furthermore, the primary endpoint was not appropriate, mixing soft events, such as revascularization, with irrevocable events such as death and MI. There was no benefit shown for MI plus CHD death.
I would not use simvastatin plus ezetimibe to treat advanced kidney disease patients based upon this trial. In such patients, evidence-based use of statins is prudent using the current guidelines for drug administration to patients at high risk for CHD.
This trial had an unfortunate design which provides no information on the value of ezetimibe. The trial should have included a statin monotherapy arm. Beyond this, the overall trial result was disappointing with no significant effect on the important endpoints of non-fatal MI or CHD death. Even if one accepts the investigators’ change in the study endpoint during the trial to a broader composite endpoint of “any major atherosclerotic event” (consisting of coronary events, strokes, and revascularization procedures) the NNT was a disappointing 48 over 4.9 years (1 event per 235 patient-years of treatment), driven primarily by revascularizations. This provides no compelling justification either on an efficacy, or likely a cost-efficacy basis, for use of a branded simvastatin/ezetimibe combination product, over statin monotherapy.
We should be careful not to generalize these results obtained with a specific drug to the overall treatment of lipid disorders in kidney disease. But, in the broad sense, the literature remains unclear whether a disease modifying approach with lipid lowering therapy is truly effective in chronic kidney disease.
SHARP doesn’t really tell us much about ezitimibe. It was not specifically designed to evaluate the incremental effect of add-on ezetimibe therapy to patients optimally treated with statins. Without an active control statin treatment arm, it is not possible to ascertain the relative contribution of ezetimibe on the overall treatment effect. What one can take away from this trial is that LDL lowering of about 33mg/dL (from a baseline level of about 108 mg/dL) achieved with a low fixed-dose of simvastatin in combination with ezetimibe is associated with a modest 2.1% absolute (0.4% per year) or 17% proportional reduction in major atherosclerotic events. To claim these as BIG BENEFITS (as stated in the press release from CTSU) is simply a case of “over-egging the pudding”. The treatment benefit was driven by reduction in revascularization (the most prevalent, but arguably the least clinically important endpoint) and non-hemorrhagic stroke, without significant benefit in coronary death or nonfatal MI. There were numerically higher, but not statistically significant, number of all cause deaths and cancer-related deaths in the active treatment arm, and the main renal endpoint (progression to ESRD) was not significantly different.
If one is hesitant to use high-dose statins in advanced or end-stage renal disease patients because of heightened risk of muscle- or liver-related adverse events, then this trial provides some reassurance that a low, fixed-dose statin, in combination with ezetimibe might be an effective and safe alternative. However, one could argue that similar reduction in LDL levels and secondary “atherosclerotic outcomes” were observed with 20 mg atrovastatin alone in 4D trial (the primary results failed to yield overall treatment benefit in 4D) which enrolled a much higher-risk patient population as reflected in a nearly 5-fold greater risk of vascular mortality per year. Bottom line, without a direct head-to-head comparison trial, one cannot draw definitive conclusions about the comparative effectiveness and safety of low, fixed-dose statin plus ezetimibe versus higher-dose statin alone in patients with advanced kidney disease.
Simvastatin is a good drug, but atorvastatin showed the same benefits in the The German Diabetes and Dialysis Study (4D) trial. SHARP tells us nothing about ezetimibe.
This study does not answer the question of whether or not they would have gotten the same result if they used simvastatin alone (ie, if ezetimibe had anything to do with the observed results) or if ezetimibe is safe. But, it is notch on the belt in favor of the drug, because it is a RCT that used ezetimibe and reduced events.
The 4D trial showed significant reductions in “all cardiac events” with atorva 20 mg daily – so it is an overstatement to say that they are “first and only prospective clinical study in patients with chronic kidney disease” to reduce atherosclerosis-related cardiac events as they did in their press release. The paper refined that to say “two trials of statin therapy “had not detected significant benefits in their primary outcomes.” True enough, but not very compelling since the SHARP investigators changed their primary endpoint to essentially the secondary endpoint in 4D. Indeed, the secondary endpoint in 4D (“all cardiac events”) was essentially the primary endpoint in SHARP. Atorvastatin had a similar relative benefit (18%) but a greater absolute difference (6% vs 2%). The p value was higher because the study was a lot smaller) Rosuva 20 mg in AURORA did not show a benefit, but AURORA and 4D subjects were very different than those in SHARP. All were on dialysis. Only 1/3 of SHARP were, so they had less advanced kidney disease and were less likely to die of dialysis-related problems (including cardiac) and more likely to die of atherosclerosis complications. The differences lie in the study populations, causes of death, degree of kidney disease. Also, we already knew that those with GFR from 30-60 had CVD reductions from the pravastatin meta-analysis, so this result is completely expected. I think patients with advanced kidney disease will benefit from statin therapy, if their life expectancy is long enough to see benefits. The magnitude of the benefit probably is lower once they are on dialysis, but it is important when people have advanced but not dialysis-dependent CKD.
June 10th, 2011
A New Biomarker From the Lungs
Larry Husten, PHD
A new study raises the possibility that a protein produced in the lungs may improve the prediction of cardiovascular disease. In a paper in the European Journal of Cardiology, John Hill and colleagues report on their research with surfactant protein-D (SP-D). Produced in the lungs, SP-D levels increase in the general circulation following lung injury and lung inflammation.
The researchers measured SP-D levels in 806 patients undergoing coronary angiography to determine its value in predicting cardiovascular risk. They then measured SP-D levels in a replication cohort of 4,468 current and former smokers with no known history of coronary disease.
SP-D levels were significantly higher in the patients who died during followup than in survivors (median 85.4 vs. 64.8 ng/mL; p<0.0001). The risk of dying was 4.4-fold higher among those in the highest SP-D quintile compared to those in the lowest quintile. This effect was independent of age, sex, and lipids.
The authors point out that there are currently no generally accepted biomarkers for chronic lung inflammation, although chronic lung inflammation is known to be closely tied to CV risk and mortality. The study was unable to assess whether SP-D is a biomarker for, or plays an active role, in CVD. They speculate that SP-D plays an important anti-inflammatory and anti-oxidant role in the lungs, but may have an adverse atherogenic effect in the systemic circulation. They conclude:
“…we found that circulating SP-D levels are strongly predictive of future risk of cardiovascular mortality, independent of well-established risk factors. These data implicate lung inflammation in the pathogenesis of heart and blood vessel disease and raise the possibility of using this protein as a biomarker to risk stratify CVD patients above and beyond traditional risk factors such as serum cholesterol and C-reactive protein.”
in the lungs
June 10th, 2011
TAVR: A Stroke of Genius or Bad Luck?
Richard A. Lange, MD, MBA and L. David Hillis, MD
After presentations at the ACC and American Association for Thoracic Surgery 2011 meetings, the PARTNER A results are finally published. PARTNER A compared transaortic valve replacement (TAVR, also known as TAVI) with surgical aortic valve replacement (AVR) in patients with aortic stenosis who were eligible for AVR but considered to be at high surgical risk .
At 1-year follow-up, survival and symptom improvement were similar with the two procedures, but the stroke rate was higher with TAVR (6.0% vs. 3.1%). What do we know about TAVR-associated strokes?
- The smaller the valve area, the higher the stroke risk.
- Patients with “generalized heavy arteriosclerotic burden” (i.e., those whose severe PAD renders them ineligible for the transfemoral approach) have a higher stroke risk than those with lighter atherosclerotic burdens; however,
- Stroke risk was unrelated to atrial fibrillation or TAVR approach (transapical vs. transfemoral).
- With TAVR, the hazard for stroke was seen early (within 48 hrs of the procedure) and remained elevated throughout the 24 months of follow-up, but AVR-associated strokes occurred early.
Based on these data, how would you choose which procedure — AVR or TAVR — to recommend for your patients?
June 9th, 2011
Pioglitazone (Actos) Suspended in France Over Cancer Concerns
Larry Husten, PHD
Sales of the popular diabetes drug pioglitazone (Actos, Takeda) have been suspended in France after a study carried out by the French health insurance fund (CNAM) found that it may increase the risk of bladder cancer. The French regulatory agency (AFSSAPS) said that new prescriptions for drugs containing pioglitazone may no longer be written, but that people who are already taking the drug may continue to do so.
Pioglitazone is the subject of an ongoing FDA safety review for a potential increased risk of bladder cancer after 2 years of exposure. The FDA has not commented on the French action. The European Medicines Agency (EMA) announced in March that it was also conducting a safety review of pioglitazone. The EMA today issued a statement about the French suspension and said that pioglitazone will be discussed at the next Committee for Medicinal Products for Human Use (CHMP) meeting on June 20-23, 2011, and that it will “recommend appropriate actions as necessary” at that time. For now, the EMA “is not recommending any changes to the use of pioglitazone-containing medicines.”
June 8th, 2011
SHARP Results Published in Lancet
Larry Husten, PHD
The main results of SHARP (Study of Heart and Renal Protection) have now been published in the Lancet, following their preliminary presentation last November at the American Society of Nephrology meeting. The results are also posted online on the trial’s website.
In brief, SHARP randomized 9270 patients with chronic kidney disease (CKD) — one-third of whom were on dialysis — to either placebo or the combination of simvastatin and ezetimibe. After a median followup of 4.9 years, the rate of major atherosclerotic events (defined as nonfatal MI or coronary death, nonhemorrhagic stroke, or arterial revascularization excluding dialysis access procedures) was significantly lower in the combination therapy group (11.3%) than in the placebo group (13.4%; RR 0.83, CI 0.74-0.94, p=0.0021).
For the individual components of the endpoint, there were nonsignificant differences in nonfatal MI (3.4% for placebo vs. 2.9% for combination therapy, p=0.12) and CHD death (1.9% vs. 2%, p=0.95). Significant differences were observed between the placebo and combination groups for nonhemorrhagic stroke (3.8% vs. 2.8%; p=0.01) and revascularizations (7.6% vs. 6.1%, p=0.0036).
In their discussion, the SHARP investigators said that the SHARP results are “relevant… to most patients with chronic kidney disease” because “the proportional reduction in major atherosclerotic events produced by a given absolute reduction in LDL cholesterol is broadly similar irrespective of age, sex, diabetes, history of vascular disease, and presenting lipid profile.”
The authors further wrote that because previous trials with statins have found that the reduction in risk “is chiefly determined by the absolute reductions in LDL cholesterol,” and because ezetimibe “reduces LDL cholesterol by the equivalent of around three doublings of the statin dose,” ezetimibe “therefore offers a potentially useful method of increasing benefits in high-risk populations.”
In an accompanying comment, Kathryn Stevens and Alan Jardine offer a “pragmatic interpretation” of SHARP and recommend the use of lipid-lowering therapy in CKD patients, “including those who will progress to end-stage renal disease.” They note, however, that coronary disease plays only a relatively small role in the deaths of patients with advanced CKD, thereby limiting the ultimate effect of lipid lowering therapy in this group of patients.
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