Oliver Weingartner and colleagues have a letter in the current issue of JAMA, responding to the publication of a trial of the “portfolio diet” of cholesterol-lowering foods, including margarine fortified with plant sterols.
To the Editor: In their study on dietary strategies to reduce serum cholesterol levels, Dr Jenkins and colleagues concluded that a dietary portfolio including plant sterols resulted in greater reductions in low-density lipoprotein cholesterol (LDL-C) levels during a 6-month follow-up compared with low-saturated-fat dietary advice. Although a significant LDL-C lowering achieved by a dietary portfolio including plant sterols may be beneficial, we believe the results do not necessarily support a heart health benefit. In Table 3 of the article, the plant sterol–fortified dietary portfolio reduced serum cholesterol levels at the expense of an increase of plasma plant sterol levels (10.7 μmol/L at baseline and 13.3 μmol/L at week 24). (To convert phytosterols to mg/dL, multiply by 0.04.)
Our research group has previously assessed the effect of lipid lowering with ezetimibe or phytosterols in apolipoprotein E (apoE) −/− mice. We found that plasma plant sterol concentrations were strongly correlated with increased atherosclerotic lesion formation (r = 0.50), suggesting that plant sterols may be atherogenic. Based on a rare inherited disease called phytosterolemia, characterized by overabsorption of phytosterols and premature coronary artery disease, and several epidemiological studies that have shown a correlation between increased plant sterol plasma levels and cardiovascular risk, the role of plant sterols in the management of hypercholesterolemia has become controversial. Studies assessing hard cardiovascular end points are needed before conclusions that a diet enriched with plant sterols reduces cardiovascular risk can be drawn. (citations omitted)
The essential point, as made by many people in recent years (see, e.g., this commentary), is that it is not enough to show that an intervention lowers LDL (or raises HDL, etc.). Before we can be sure that the intervention is beneficial, we need evidence that it lowers the risk of heart attacks and strokes.
In their reply, Vanu Ramprasath and colleagues note that some epidemiological and animal studies have not found risk associated with increased plant sterol levels and the fact that statins may increase absorption of plant sterols. In summary, they state that “based on evidence from both humans and animal models, we believe that plant sterol levels in plasma are not related to increased CHD risk.”
A comment about this summary statement. There really is no controversy about whether high levels of plant sterols cause heart disease: because of the association of premature heart disease with the rare genetic disease sitosterolemia, everyone agrees that they do. The issue is whether more moderate increases in plant sterol levels are harmful.
So the controversy continues.
I have a guest post up at Merrill Goozner’s blog explaining why Merck’s application for a new indication for its drugs Vytorin (simvastatin/ezetimibe) and Zetia (ezetimibe) should not be approved. The proposed indication is for the reduction of major cardiovascular events in patients with chronic kidney disease and is based on the results of the SHARP trial. However, because SHARP compared the combination of simvastatin and ezetimibe with placebo — there was no simvastatin arm — we have no way of knowing if ezetimibe contributed anything to the result. The FDA requires that combination drugs have additive effects over either drug alone. Merck has not shown that ezetimibe contributed anything to the effect in SHARP, so the new indication should not be approved.
Addendum January 25, 2012: Merck issued a press release today stating that the FDA did not approve the new indication. “Because SHARP studied the combination of simvastatin and ezetimibe compared with placebo, it was not designed to assess the independent contributions of each drug to the observed effect; for this reason, the FDA did not approve a new indication for VYTORIN or for ZETIA® (ezetimibe) and the study’s efficacy results have not been incorporated into the label for ZETIA.” The SHARP results were incorporated into the Vytorin label (see pages 27-28).
I have a guest post up on Gary Schwitzer’s blog critiquing Sanjay Gupta’s promotion of calcium scans and overhyping of extreme diets.
People often get the wrong tests, wasting resources and often leading to inappropriate treatment.
Angioplasty is overused in nonemergency situations when lifestyle changes and drugs would be just as effective.
Consumers don’t have enough information on quality of care.
The nature of heart disease is often misunderstood to be a kind of plumbing problem. This leads to the idea that the way to prevent future problems is to search for blockages and stent them. This procedure can be lifesaving in a patient who is in the midst of a heart attack, but has not been shown to be more beneficial in nonemergency situations than a more conservative approach of controlling risk factors with lifestyle changes and drugs.
In addition, CR found in a survey of 8,000 of its subscribers that many people undergo heart-related screening tests such as an electrocardiogram, exercise stress test, or ultrasound of the carotid arteries, “even though such tests aren’t recommended for healthy people.” In addition, many people undergo these screening tests without first investigating the accuracy of the tests or what they would need to do if the test indicated a possible problem.
Addendum August 17, 2011: The Cleveland Clinic had an online health chat on coronary artery disease treatments yesterday, so I took the opportunity to ask Dr. Steven Nissen a question. Here’s my question and his answer:
marilynmann_1 asks: The September 2011 issue of Consumer Reports recommends that a sedentary middle-aged person with cardiac risk factors, who is asymptomatic, get a stress test before starting an exercise program. Do you concur?
Dr__Steven_Nissen: No. It’s sensitivity is about 60% and its specificity is about 60% in patients without symptoms – therefore it is slightly better then a flip of a coin. If the test is positive it may lead to unnecessary further studies that may lead to procedures that are not indicated.
In a recent post, I discussed a panel discussion on May 14, 2011, at the American Heart Association Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke conference. The discussion addressed lessons from experiences with three drugs that were withdrawn or greatly restricted because they caused cardiovascular (CV) harm — rofecoxib (Vioxx), rosiglitzone (Avandia) and sibutramine (Meridia). I summarized the introduction by Sanjay Kaul and the presentations by Steve Nissen and Milton Packer. In this post I will discuss the presentations by statistician Dean Follmann of National Institute of Allergy and Infectious Diseases, NIH, and Ellis Unger of the Center for Drug Evaluation and Research, FDA.
Follmann’s presentation was similar to one he gave at the July 2010 joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee that was held to discuss Avandia. Follmann discussed the hierarchy of study designs, with randomized controlled trials (RCTs) that are double blind superiority trials being at the top. In such a design, randomization ensures that the groups are similar and double blinding ensures that the investigators can’t favor one arm over another. In addition, in a superiority trial the incentives encourage good study conduct because sloppiness (e.g. missing data, loose inclusion criteria, lack of adherence) makes it more difficult to show that the drug is effective. At the next level of reliability, according to Follman, are RCT noninferiority trials and meta-analyses. In a noninferiority trial, the goal is to conclude that a drug is not “unacceptably worse” than a comparator. In Follmann view, the incentives in a noninferiority trial “encourage sloppiness,” since sloppiness will tend to make the two arms more similar and thus meet the goal of noninferiority. (The RECORD trial was a noninferiority trial and was used to assess the safety of Avandia.) A meta-analysis is a quantitative synthesis of RCTs. In Follmann’s view, the quality of evidence of a meta-analysis is a bit less than a RCT, because (1) there may be unpublished trials that are not available for inclusion in the meta-analysis, (2) studies may be heterogeneous in population, endpoints, and comparators, and (3) the decisions on how to conduct the meta-analysis (e.g., what to include, how to analyze, endpoint definition) are made with knowledge of the potential safety signal. For example, to counter the Nissen-Wolski and FDA Avandia meta-analyses, which used myocardial infarction (MI) as the endpoint, GlaxoSmithKline chose a wider endpoint of serious and nonserious ischemia, resulting in a smaller hazard ratio. In addition, GSK used a “very unconventional and some would say illegitimate method of analyzing the data,” according to Follmann. Follmann also stated that it was a “revelation” to him to learn from Nissen’s presentation that GSK had done previous meta-analyses that had similar results as the Nissen-Wolski meta-analysis.
Follmann stated that the next study type in the hierarchy is observational studies. Because, observational studies are not randomized, drug choice may be based on patient characteristics, doctor preference, and unquantifiable factors. Statistical adjustment is done, but the result is less reliable than a RCT. Below observational studies are the FDA’s Adverse Event Reporting System (AERS) and data collected for other purposes, such as data collected by HMOs or the Centers for Medicare & Medicaid Services (CMS). In summary, Follmann stated that assessing a post marketing safety signal is difficult. RCTs are the best data source but are not always available.
Ellis Unger’s first remark was that Nissen had a “retrospectoscope in his back pocket” and was being a “Monday morning quarterback” with respect to the FDA’s actions concerning Vioxx and Avandia. He pointed out that the FDA has to make decisions in real time, which is not so easy, and he is not convinced that the FDA did the wrong thing, based on what it knew at the time. He does agree with the ultimate outcome for Vioxx, Avandia and Meridia.
With respect to Vioxx, Unger stated that at the time of approval it was known that there were associations between Vioxx and hypertension and edema, but in the preapproval trials there were no differences with respect to MI and stroke. The VIGOR trial showed a hazard ratio of 1.94 for the composite endpoint of death, MI and stroke. For non-fatal MI, the hazard ratio was 4.51 (p < 0.05). He does not believe the VIGOR data were enough that Vioxx should have been removed from that market at that point (2000). Unger next discussed the APPROVe trial, which was stopped two months early due to an excess in serious thrombotic events in the Vioxx group (RR 1.92), and resulted in the voluntary removal of Vioxx from the market. In the wake of Vioxx’s withdrawal, the FDA held a joint meeting of the Arthritis and Drug Safety and Risk Management Advisory C0mmittees on February 16-18, 2005 to discuss Cox-2 inhibitors. Unger summarized the data presented at the meeting as follows: (1) “all Cox-2-selective agents seem to increase CV risk (no ranking)” and (2) “available data do not support greater CV risk for selective agents as compared to non-selective agents.” After the meeting, the FDA added labeling warning of the potential for increased risk of CV thrombotic events to all NSAIDs.
With respect to rosiglitazone, Unger stated that the evidence of cardiovascular risk is “neither robust nor conclusive” and “remains an open question,” while acknowledging that there were “multiple signals of concern from various sources of data, without reliable evidence to refute risk.” He stressed the limitations of the Nissen/Wolski meta-analysis, including that the results were based on a relatively small number of events. Interestingly, Unger said that the FDA was more worried about the finding for cardiovascular death (odds ratio 1.64, p = 0.06) than the finding for MI (odds ratio 1.43, p = 0.03), even though the result for CV death was not statistically significant. Unger views the ADOPT and DREAM trials as being neutral on cardiovascular death, with both showing trends for increased MI.
With respect to the RECORD trial, Unger criticized the open-label design and possibility of ascertainment bias but also stated that the results for all-cause death are “unlikely to be influenced by bias,” and showed a favorable trend for rosiglitazone. With respect to MI, the results were “inconclusive,” as neither the GSK nor the FDA analysis showed a statistically significant increase in MIs. Unger stated that viewed as a means to test the two hypotheses generated by the Nissen/Wolski meta-analysis — rosiglitazone causes MI and increases the risk of CV death — RECORD “does not substantiate the findings of the Nissen/Wolski meta-analysis.” (For more on Unger’s views on RECORD, see his slides from the 2010 advisory committee meeting on rosiglitazone here). Finally, Unger noted that the David Graham epidemiological study of Medicare patients did not find a statistically significant higher risk of MI with rosiglitazone as compared to pioglitazone. Why didn’t the FDA take rosiglitazone off the market instead of leaving it on the market with restricted access? Unger cited conflicting data on the existence and magnitude of risk, the need for detailed re-adjudication and analysis of RECORD, the fact that some patients are currently taking rosiglitazone and want to stay on it even with knowledge of the risk.
With respect to sibutramine (Meridia), a weight loss drug that is an inhibitor of norepinephrine, serotonin and dopamine reuptake, Unger noted that at approval in 1997 the drug was known to increase blood pressure and heart rate and result in miscellaneous ECG changes, but the adverse effects were deemed “monitorable.” The European regulators, however, required a post-marketing cardiovascular outcomes study. This was the SCOUT trial, a large randomized, double-blind, placebo-controlled trial in obese patients over age 55 with a history of coronary artery disease, peripheral vascular disease, or stroke and/or Type 2 diabetes with at least one other risk factor. The primary endpoint was a composite of CV death, resuscitation after cardiac arrest, non-fatal MI and non-fatal stroke, which occurred in 11.4% of the patients on sibutramine and 10.0% of the patients on placebo (HR 1.16, p = 0.02). Following this trial, sibutramine was removed from the market in the U.S. and Europe.
Unger noted that post-marketing safety used to focus on rare, severe events that were detectable from spontaneous reporting. In recent years, there has been greater interest in small increases in common but serious events, such as MI, stroke, and CV death. Quantification of common risks is challenging with longer, larger studies required. If the drug is for a symptomatic condition such as depression or pain, it is difficult to keep patients from dropping out of the trial. It is difficult to interpret the results of a trial when there have been a lot of dropouts.
Unger stated that when the FDA reviews clinical trial data they are interested in imbalances in virtually any safety issue so we “always see safety signals because we look at 150 adverse events.” They have to consider a number of issues in assessing causality: whether there is a plausible mechanism of action, whether it has been observed in other related drugs, whether there is a dose-response relationship, etc.
Comment: I think the problem of post approval safety is not entirely solvable, because there will always be safety signals that crop up after drugs are approved. However, I am in sympathy with Dr. Nissen’s view that safety signals should be investigated and acted on as early as possible, and preferably before approval.
Also, on the topic of Vioxx specifically, I suggest the following for further reading:
Joseph S. Ross, MD, MHS; Kevin P. Hill, MD, MHS; David S. Egilman, MD, MPH; Harlan M. Krumholz, MD, SM. Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents From Rofecoxib Litigation. JAMA. 2008;299(15):1800-1812.
Keven P. Hill, MD, MHS; Joseph S. Ross, MD, MHS; David S. Egilman, MD, MPH; Harlan M. Krumholz, MD, SM. The ADVANTAGE Seeding Trial: A Review of Internal Documents. Annals of Internal Medicine. 2008;149(4):251-258.
Joseph S. Ross, MD, MHS; David Madigan, PhD; Kevin P. Hill, MD, MHS; David S. Egilman, MD, MPH; Yongfei Wang, MS; Harlan M. Krumholz, MD, SM. Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial Data: Lessons for Postmarket Pharmaceutical Safety Surveillance. Archives of Internal Medicine. 2009;169(21): 1976-1985.
Joseph S. Ross, MD, MHS; David Madigan, PhD; Marvin A. Konstam, MD; David S. Egilman, MD, MPH; Harlan M. Krumholz, MD, SM. Persistence of Cardiovascular Risk After Rofecoxib Discontinuation. Archives of Internal Medicine. 2010;170(22):2035-2036.
Snigdha Prakash, All the Justice Money Can Buy: Corporate Greed on Trial (2011) (book by former NPR reporter Snigdha Prakash on the Vioxx saga — focuses on a particular Vioxx trial).
Like my last post, this post is inspired by Harriet Hall’s recent review of The Mayo Clinic Book of Home Remedies on the Science-Based Medicine blog. For elevated cholesterol, the book recommends trying “natural products,” including garlic.
In 2007, the results of a randomized controlled trial of garlic on cholesterol concentrations on adults with moderate hypercholesterolemia were reported in Archives of Internal Medicine. The trial evaluated raw garlic and two commonly used garlic supplements. None of the forms of garlic, including raw garlic, when given at an approximate dose of a 4 gram clove per day, 6 days a week for 6 months, had statistically or clinically significant effects on LDL-C or other plasma lipid concentrations.
In addition, a meta-analysis was published in 2008 that did not find beneficial effects of garlic on total cholesterol, LDL, triglycerides, or apoB.
Based on the above, it seems like a waste of time and effort for anyone to try to lower their cholesterol with garlic.
Gardner, et al., Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: a randomized clinical trial. Arch Intern Med. 2007;167(4):346-353.
Khoo, et al., Garlic supplementation and serum cholesterol: a meta-analysis. Journal of Clinical Pharmacy and Therapeutics. Volume 34, Issue 2, pages 133–145, April 2009.