November 19th, 2012
Comprehensive Guidelines for Stable Ischemic Heart Disease Released
Larry Husten, PHD
Stephan D. Fihn, MD
New comprehensive guidelines for the diagnosis and treatment of stable ischemic heart disease have been released by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Task Force on Practice Guidelines, along with the American College of Physicians (ACP), American Association for Thoracic Surgery (AATS), Preventive Cardiovascular Nurses Association (PCNA), Society for Cardiovascular Angiography and Interventions (SCAI), and the Society of Thoracic Surgeons (STS). The guidelines are being published in the Journal of the American College of Cardiology and Annals of Internal Medicine and will be available on the ACC Cardiosource website and the SCAI website.
The chairman of the writing committee, Stephan Fihn, provided the following summaries of the key points of the document for professionals and for patients:
For professionals:
a. Management of stable ischemic heart disease (IHD), including diagnosis, risk assessment, treatment and follow-up should be based upon strong scientific evidence and the patient’s preferences.
b. All patients who present with angina should be categorized as stable vs. unstable angina. Those with moderate- or high-risk unstable angina should be treated emergently for acute coronary syndrome.
c. For patients with an interpretable ECG and who are able to exercise, a standard exercise test should be the first choice test for diagnosis of IHD, especially if the likelihood is intermediate (i.e., 10% to 90%). Those who have an uninterpretable ECG and are able to exercise should undergo an exercise stress with nuclear myocardial perfusion imaging (MPI) or echocardiography, particularly if the likelihood of IHD is intermediate to high. For patients unable to exercise, nuclear MPI or echocardiography with pharmacologic stress is recommended.
d. Patients diagnosed with stable IHD should undergo assessment of risk for death or complications of IHD. For patients with an interpretable ECG and who are able to exercise, a standard exercise test is also the preferred choice for risk assessment. Those who have an uninterpretable ECG and are able to exercise should undergo an exercise stress with nuclear MPI or echocardiography, while for patients unable to exercise, nuclear MPI or echocardiography with pharmacologic stress is recommended.
e. Patients with stable IHD should generally receive a “package” of Guideline-Directed Medical Therapy (GDMT) that includes lifestyle interventions and medications shown to improve outcomes, including (as appropriate):
- Diet, weight loss, and regular physical activity;
- If a smoker, smoking cessation;
- Aspirin 75 mg – 162 mg daily;
- A statin medication in moderate dosage;
- If hypertensive, antihypertensive medication to achieve BP <140/90 mm Hg;
- If diabetic, appropriate glycemic control.
f. Patients with angina should receive sublingual nitroglycerin and a beta-blocker. When these are not tolerated or are ineffective, a calcium-channel blocker or a long-acting nitrate may be substituted or added.
g. Coronary arteriography should be considered for patients with stable IHD whose clinical characteristics and results of noninvasive testing indicate a high likelihood of severe IHD and when the benefits are deemed to exceed risk.
h. The relatively small proportion of patients who have “high-risk” anatomy (e.g., >50% stenosis of the left main coronary artery), revascularization with CABG should be considered to potentially improve survival. Most of the data showing improved survival with surgery compared to medical therapy are several decades old and based on surgical techniques and medical therapies that have advanced considerably. There are no conclusive data demonstrating improved survival following PCI.
i. For the vast majority of patients with stable IHD, a trial of GDMT is warranted before consideration of revascularization to improve symptoms. Deferral of revascularization is not associated with worse outcomes.
j. Prior to performing revascularization to improve symptoms, coronary anatomy should be carefully correlated with functional studies to ensure the highest likelihood that lesions responsible for symptoms are targeted.
k. All patients with stable IHD should receive careful follow-up to monitor for progression of disease, complications, and adherence to therapy. Exercise and imaging studies need not be performed annually and should generally be repeated only when there is a change in clinical status or when clinical features suggest a significant change in risk of death or complications from IHD.
For patients:
a. Nearly 9 million people in the U.S. have angina, the most common symptom of IHD, and the prevalence is as high as 15% to 33% among persons over age 60.
b. If you develop chest discomfort or shortness of breath with activity, seek immediate medical attention.
c. The choice of tests to diagnose IHD is complicated and is based upon your symptoms and your personal and health characteristics and preferences. If you are able to exercise, a standard exercise test is often the first-choice test.
d. If you are found to have IHD, it is important for your physician to assess your risk for a heart attack or other undesirable outcomes. This may require additional exercise or imaging tests.
e. Most patients with IHD should adopt lifestyle changes that include a healthy, low-fat diet; regular exercise; and, when warranted, weight loss. Other important steps (when applicable) include: smoking cessation; good control of high blood pressure; a statin medication to lower LDL (bad) cholesterol; good control of diabetes; daily aspirin; and medications to eliminate chest pain (angina) such as nitroglycerin and beta-blockers. This “package” of activities and medications is called Guideline-Directed Medical Therapy.
f. When angina does not respond to medications, patients may decide with their medical team to undergo a procedure to improve circulation to the heart. This can be accomplished either with surgery (coronary artery bypass grafting) or with a catheter (PCI – percutaneous coronary intervention). The choice should be based on the clinical characteristics of the patient and the results of testing, including cardiac catherization. Both surgery and PCI are relatively safe and effective in eliminating chest pain, BUT surgery improves survival only in a relatively small group of patients with very severe blockages of the left-main coronary artery or several arteries, whereas PCI has not been conclusively shown to improve survival in any group of patients.
g. Patients with stable IHD should receive regular medical follow-up from a primary care provider or cardiologist. The purpose is to answer any questions that arise, monitor therapy for effectiveness and possible adverse events, and check for any new complications related to IHD. Annual stress tests are usually not necessary, and your provider should determine what tests are necessary and how often they should be performed based upon your personal clinical characteristics.
November 19th, 2012
Selections from Richard Lehman’s Literature Review: November 19th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
JAMA 14 Nov 2012 Vol 308
Multivitamins and Cancer Prevention in Men (pg. 1916): Last week we learned that male doctors who were randomised to take a daily multivitamin preparation had cardiovascular events and died from them at exactly the same rate as those who took placebo for a median of 11.2 years. This week we learn that they also died of cancer at the same rate, but by aggregating all the cancers you can just squeeze a statistically significant reduction in total cancer incidence out of the data. So come on, fellow male physicians: if 83 of us take a daily multivitamin for 11 years, one of us may avoid a cancer, though all of us will die at the same rate. Golden docs in trials all must/ As chimney-sweepers, come to dust.
Atorvastatin with or without a PCSK9 Antibody in Primary Hypercholesterolemia (pg. 1891): After a while, it gets a bit boring restating the fact that the only lipid lowering agents which have been shown to reduce clinical events are the statins. I believe that this is true of people with primary hypercholesterolaemia as well as of the general population, but if I am wrong, I know I will quickly be corrected. The most potent dose of statin that most people can tolerate is atorvastatin 80mg, but in some individuals even this is not enough to reduce LDL-C sufficiently. In this phase 2 trial, Sanofi and Regeneron Pharmaceuticals tried out their new monoclonal antibody targeted at serum proprotein convertase subtilisin/kexin 9 (PCSK9), which has the effect of reducing degradation of LDL receptors and so gets more LDL removed from the circulation. This sounds very neat and ingenious, and it does actually work: SAR236553 lowers LDL-C more in primary hypercholesterolaemia than does atorvastatin 80mg, and can be added to it for extra effect. Time to give it a catchy name and start marketing it? I would say not. Just because monoclonal antibodies sound like magic bullets, that doesn’t mean that they are either harm-free or as effective as surrogate end-point reduction would suggest. In the real world, there is no substitute for real time and real results: we need quite lengthy phase 3 studies.
Lancet 17 Nov 2012 Vol 380
Type-2 Diabetes Screening and Population Mortality Over 10 Years (pg. 1741): Here is one of the most important papers to have come out of UK general practice for some years. It reports a cluster randomised trial with 9.6 years of follow-up which shows that screening for diabetes in high risk individuals has no benefit. It used a validated risk score to identify 15,000 individuals at risk who were offered screening, with a control group of 4,137 who were not. Individuals identified with diabetes were then randomized to usual care or intensive multifactorial treatment. I know that at least one of the investigators was expecting the trial to demonstrate benefit, but there was simply no reduction in all-cause, cardiovascular, or diabetes-related mortality within 10 years. And this trial not only shows a lack of benefit from the early detection of diabetes, but also casts grave doubt on the doctrine of a “legacy effect” from early tight control, as claimed by the UKPDS investigators.
BMJ 17 Nov 2012 Vol 345
Primary and Secondary Prevention with New Oral anticoagulants for Stroke Prevention in AF: The newer anticoagulants are at least as good as warfarin for the primary and secondary prevention of stroke in atrial fibrillation, but it is hard to know which is best among them—the direct thrombin inhibitors (dabigatran) and the factor Xa inhibitors (for example, rivaroxaban, apixaban). Several cardiovascular academics here look at the differences between them in the trials and reach the conclusion that only head-to-head new trials will tell us anything substantive.
Arch Int Med 12 Nov 2012 Vol 172
New Oral Anticoagulants in Patients Receiving Antiplatelet Therapy After ACS (pg. 1537): The Archives are beginning to annoy me, by printing too many interesting papers which I have to report on. Here is a piece with the cumbrous title “Use of New-Generation Oral Anticoagulant Agents in Patients Receiving Antiplatelet Therapy After an Acute Coronary Syndrome: Systematic Review and Meta-analysis of Randomized Controlled Trials.” Those of you who have been following these reviews for some years (or actually reading the primary literature—heaven forbid) will know what a keenly fought-over field this is. But for pharma companies hoping for their next blockbuster drug, a very disappointing one. “The use of anti-Xa or direct thrombin inhibitors is associated with a dramatic increase in major bleeding events, which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS” is the conclusion of these Hungarian meta-analysts. How dramatic? Well, at least three-fold: not quite all the rooms in Bluebeard’s castle, but enough to warn you off opening any more doors.
Prediction Rule for Death and Severe Disability After Acute Ischemic Stroke (pg. 1548): Now here is a hen’s tooth: a clinical prediction rule that doctors may actually use. It is called the PLAN Score and it is a bedside prediction rule for death and severe disability following acute ischaemic stroke. Not the first ever, of course, but perhaps the least cumbersome, factoring in just 9 easily available clinical variables. It had a C statistic (look this up if you don’t know what it is) in the mid 0.8 range for death by 30 days, severe dependence, and death within one year.
Drugs that Target the Renin-Angiotensin-Aldosterone System and Risk for Angioedema (pg. 1582): Angio-oedema is a common side effect of angiotensin-converting enzyme inhibitors (ACEIs) and this American database study seeks to compare these with angiotensin receptor blockers (ARBs), and much less-used the direct renin inhibitor aliskiren, while adjusting for a range of possible confounding factors. It’s a reasonable study which reaches the conclusion you’d expect: ARBs are less likely to cause your face to swell up while aliskiren is too seldom used for us to be sure, but it’s probably worse than ACEIs. Researchers using the vastly bigger UK Clinical Research Database should be churning out this kind of thing by the shedload every week.
November 15th, 2012
FDA Approves Zilver PTX Drug-Eluting Stent for Peripheral Arterial Disease
Larry Husten, PHD
The FDA today approved Cook Medical’s Zilver PTX stent. It is the first drug-eluting stent (DES) approved for the treatment of peripheral arterial disease (PAD) in the superficial femoral and proximal (i.e., above the knee) popliteal artery. The new stent will provide a new treatment option for patients with PAD. Current treatments include exercise, drug therapy, balloon angioplasty, bare-metal stents, and surgical bypass.
“The clinical study demonstrated that the Zilver is more effective than balloon angioplasty for the treatment of symptomatic peripheral artery disease in above-the-knee femoropopliteal artery,” said Christy Foreman, of the FDA’s Center for Devices and Radiological Health, in an FDA press release. “This approval expands the treatment options for patients suffering from symptomatic peripheral artery disease to include the Cook Zilver PTX drug eluting stent.”
The FDA said the Zilver PTX stent is contraindicated in people with “stenoses that cannot be dilated to permit passage of the catheter or proper placement of the stent, patients who cannot receive recommended drug therapy due to bleeding disorders, or women who are pregnant, breastfeeding, or plan to become pregnant in the next five years.” In clinical studies, the most common major adverse event associated with the stent was restenosis requiring treatment to restore patency.
The FDA is requiring Cook Medical to perform a 5-year post-approval study of 900 patients.
“This approval marks the start of Cook’s program to bring the benefits of drug elution to U.S. physicians treating the peripheral arteries,” said Cook Medical executive Rob Lyles. He added that Cook Medical intends by the end of 2013 to offer a “full suite of drug-eluting peripheral stents in the most commonly used lengths and diameters.” The Zilver PTX will be initially available in an 80-mm length in 6-mm and 7-mm diameters. The company has also received approval to market 40- and 60-mm-length stents, though these will not be available until early 2013. Cook said that it expects to receive FDA approval for a 120-mm-length stent next year.
November 15th, 2012
In Acute VTE, Novel Oral Anticoagulants and Conventional Therapy Show Similar Efficacy
Nicholas Downing, MD
Novel oral anticoagulants and vitamin K antagonists offer similar protection against venous thromboembolism recurrence, according to a BMJ meta-analysis. However, one of the newer agents, rivaroxaban, seems to offer better protection against bleeding.
The analysis included nine randomized controlled trials comparing apixaban, dabigatran, rivaroxaban, or ximelagatran (no longer on the market) with traditional vitamin K antagonists (e.g, warfarin) in nearly 17,000 patients with acute VTE. Follow-up ranged from 2 weeks to 12 months.
There were no significant differences between any of the novel anticoagulants and vitamin K antagonists with respect to recurrent VTE or all-cause mortality. The newer agents tended to lower the risk for major bleeding, but only the effect of rivaroxaban was statistically significant. An indirect comparison between rivaroxaban and dabigatran did not favor either drug for any outcome.
Asked to comment, David Green of Journal Watch Oncology and Hematology said: “The benefits of the new oral anticoagulants are that monitoring is not required and there are fewer interactions with other drugs; the downside is that there are no readily available reversing agents and experience is still accumulating about effectiveness and safety in various populations.”
November 15th, 2012
Mysterious Disappearing Paper Finally Crops Up in Journal
Larry Husten, PHD
| UPDATE:
The study’s lead author, Dr. Robert H. Schneider offers a response and defense of the paper here. |
Disclosure: Larry Husten works with Dr. Harlan M. Krumholz, who is mentioned in this post, on CardioExchange. Dr. Krumholz has recused himself from all editorial discussions and decisions about CardioExchange’s coverage of this story.
Last year, in what may have been an unprecedented action, a paper on the potential cardiovascular benefits of transcendental meditation in African Americans was withdrawn by the editors of the Archives of Internal Medicine only 12 minutes before the paper’s scheduled publication in that journal. No definitive explanation was ever provided, although the journal editors and the paper’s authors said that the action was prompted by last-minute questions from reviewers at the NIH, which had helped to fund the study.
Now, a new version of the paper has been published in Circulation: Cardiovascular Quality and Outcomes. The first author is Robert H. Schneider, of the Institute for Natural Medicine and Prevention at the Maharishi University of Management, in Fairfield, Iowa. Schneider’s coauthors are from the same institution and from the Department of Medicine at the Medical College of Wisconsin in Milwaukee. It is clearly the same study of 201 African American patients randomized to transcendental meditation or health education and followed for 5.4 years, although some of the numbers have changed in important ways between the earlier and later versions. (I had obtained the earlier version as part of Archives‘ routine early release of articles to the media.)
One change involves the primary endpoint. The new paper in Circulation:CV Quality & Outcomes reports that of 52 primary-endpoint events (a composite of death, MI, or stroke), 20 occurred in the meditation group and 32 in the health-education control group. By contrast, the previous Archives version identified 51 primary-endpoint events: 20 in the meditation group and 31 in the control group.
In both papers, the difference in the primary endpoint was reported not to achieve statistical significance until after the investigators adjusted for baseline differences. The unadjusted hazard ratio (HR) for the new study was 0.64 (95% CI, 0.37–1.12; P=0.12). After adjustment for age, gender, and use of lipid-lowering medications, the HR dropped to 0.52 (95% CI, 0.29–0.92; P=0.025), apparently a statistically significant advantage of meditation.
Here are some other questions that I put directly to Circulation’s editors:
A. Were staff at AHA or Circulation: CV Quality & Outcomes ever aware that an earlier version of this paper was to appear in the Archives of Internal Medicine and withdrawn only 12 minutes before it was scheduled to go live? Should this information have been disclosed by the study authors when submitting the paper?
B. The original publication in Archives appeared to have been cancelled because of questions raised by NIH reviewers. Have the Circulation: CV Quality & Outcomes editors received any assurance that these questions have been addressed in the new paper?
C. This trial was started back in 1998 but was not registered on ClinicalTrials.gov until February 2011 (shortly before the intended Archives publication). Why wasn’t it registered earlier?
D. ClinicalTrials.gov identifies June 2007 as the final data-collection date for the primary-outcome measure. Why do the primary-endpoint numbers differ between the Archives version and the newer version of this paper?
I asked Dr. Harlan M. Krumholz, editor of Circulation: Cadiovascular Quality and Outcomes and of CardioExchange, to comment on this story. Here is the statement he offered on November 13:
We had no prior knowledge of what transpired with the Archives of Internal Medicine. The Schneider paper went through rigorous peer review, statistical review, and editorial discussions — and the authors of the article were responsive to the review process. As a result, the paper was accepted for publication, and we are going ahead as planned. If you have further questions, we suggest you contact the researchers directly.
Also on November 13, I separately asked Sanjay Kaul, of UCLA’s School of Medicine, for perspective on the paper. Not having seen Dr. Krumholz’s above response, Dr. Kaul enumerated the following points:
1. All-cause mortality constituted nearly 80% (41 of 52 events) of the primary composite endpoint. This is highly unusual, as most trials yield a higher proportion of nonfatal events than fatal events. This leads me to question the fidelity of the adjudication process to pick up nonfatal events.
2. It is difficult to attribute a nearly 50% reduction in hard CV outcomes to a <5-mm-Hg difference in systolic BP. Total anger was significantly reduced, but attributable risk of anger or emotional distress for MI or death is very small.
3. It is interesting to note that the study was originally powered for a 36% reduction in a broader endpoint but for a larger 50% reduction in the revised narrower endpoint. This is difficult to justify.
4. It is not clear whether the adjusted analyses were adjusted for multiple comparisons. Given the wide confidence interval and less than robust P-value, it is likely the results would be no longer significant.
5. Even if one accepts the adjusted P-value, the strength of evidence is not robust.
Update, November 18: An earlier version of this article contained several mistakes. First, the difference in the number of primary-endpoint events between the two papers is much smaller than I had stated. The original paper reported 51 primary-endpoint events (not 40, as I had misstated). The new paper reports 52 primary-endpoint events. I also incorrectly claimed that some data reported in the original Archives paper were not included in the published Circulation: CV Quality & Outcomes paper. In fact, these data were reported in Figure 1. I apologize for this mistake and regret the errors. –Larry Husten
November 13th, 2012
Expert Consensus Document Offers Advice on Troponin Tests
Larry Husten, PHD
A newly published document provides practical advice on the use of the popular and potent troponin tests. The Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations was developed by the American College of Cardiology Foundation in collaboration with several other societies to help address the many complex issues raised by the introduction of the tests in clinical practice.
Sanjay Kaul, a co-author of the document, said the document does not contain new information, but was written to respond to the request of clinicians “for help regarding the considerations for ordering, interpreting, and using troponin as a decision aid in the management of patients with ACS and non-ACS conditions.” The document provides “a roadmap for the proper use of troponin in the setting of appropriate clinical context. The hope is to avoid unnecessary testing and referral as well as inappropriate utilization of downstream diagnostic and therapeutic interventions.”
The document helps physicians understand when they should order troponin tests and how to interpret the results. The recommendations are designed to work in coordination with the recently updated universal definition of MI, and provide detailed information about the use of troponins in acute coronary syndromes, PCI, CABG, and a variety of nonischemic clinical conditions.
“There are many things that can cause damage to the heart muscle that would allow troponin to leak in the circulation where we can measure it, and it’s not always due to heart attack,” said L. Kristin Newby, the co-chair of the writing committee, in an ACC press release. “So if we are indiscriminate in how we order these tests or we aren’t paying attention to the clinical scenario before us, we may miss something important.”
“We need to be thinking about why we are ordering the troponin test before we order it,” said Newby. “We hope this document provides a road map to help clinicians be more deliberate when ordering these tests and interpreting the results.”
November 12th, 2012
Nonfasting Lipid Testing Gains Growing Acceptance
Larry Husten, PHD
Although fasting before a lipid test has long been recommended, a new study and accompanying commentaries make the case that nonfasting lipid levels are acceptable and may even be superior to fasting levels for the assessment of cardiovascular risk.
Investigators at the University of Calgary analyzed data from laboratory tests obtained from more than 200,000 people and found that fasting time caused little variation in total cholesterol and HDL cholesterol levels, although LDL levels and triglycerides varied by as much as 10% and 20%, respectively. The finding, the authors write in their paper in the Archives of Internal Medicine, “suggests that fasting for routine lipid level determinations is largely unnecessary,” although patients with triglyceride levels over 400 mg/dL may require a fasting lipid level or a direct measurement of LDL.
In an accompanying editorial, J. Michael Gaziano writes that “the incremental gain in information of a fasting profile is exceedingly small for total and HDL cholesterol values and likely does not offset the logistic impositions placed on our patients, the laboratories, and our ability to provide timely counseling to our patients. This, in my opinion, tips the balance toward relying on nonfasting lipid profiles as the preferred practice.”
In an invited commentary, Amit Khera and Samia Mora take note of some limitations of the study but conclude that “given the current lack of evidence for the superiority of fasting lipid testing, it is reasonable to consider nonfasting lipid testing in most individuals who present for a routine clinic visit.” Fasting levels may be indicated in people with high triglycerides and in high-risk patients such as diabetics.
November 12th, 2012
Selections from Richard Lehman’s Literature Review: November 12th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
JAMA 7 Nov 2012 Vol 308
Multivitamins in the Prevention of CVD in Men (pg. 1751): Vitamins are vital amines; you need them to stay healthy; therefore the more you take, the healthier you will be. It’s amazing how pervasive this delusion is: it led even Linus Pauling, three times Nobel prizewinner, to make an ass of himself. And it sells billions of dollars’ worth of useless tablets. Did I really see a two-storey emporium called Ye Olde Vitamin Shoppe in New York City, or had someone slipped some absinthe into my Starbucks? Anyway, you are a doctor, so you should know better than to take this rubbish: here is the Physicians Health Study II. “Among this population of US male physicians, taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up.” Antioxidants, antischmocksidants.
Platelet Function During Extended Prasugrel and Clopidogrel Therapy for ACS Treated Without Revascularization: Of course there are sound mechanistic reasons why antioxidants should prevent cardiovascular disease; it is entirely perverse that that they don’t. And there are sound mechanistic reasons why prasugrel should lead to better outcomes than clopidogrel when used with aspirin to prevent ischaemic outcomes following ACS without ST-elevation. In the TRILOGY ACS trial, patients who had not undergone revascularization had their platelet reactivity measured, and sure enough prasugrel was uniformly more effective than clopidogrel at inactivating platelets. But O perversity! “Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurrence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes.” Sound mechanistic reasons count for nothing in real life, yet again.
NEJM 8 Nov 2012 Vol 367
Statin Use and Reduced Cancer Mortality (pg. 1792): “Statin use in patients with cancer is associated with reduced cancer-related mortality. This suggests a need for trials of statins in patients with cancer.” Denmark stars again: the investigators assessed mortality among patients from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, with follow-up until December 31, 2009. They found a 15% reduction in overall mortality in people with 13 types of cancer taking statins of any kind and any dose, driven by a reduction in cancer-related mortality. So their conclusion is absolutely spot-on: we need trials of statins in cancer.
Ann Intern Med 6 Nov 2012
Comparative Effectiveness of Sulfonylurea vs. Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes (pg. 601): After the fall of the Roman Empire, the developed world entered centuries of intellectual darkness marked by minimal scientific progress, a period often called the “Dark Ages.” After many centuries, progress resumed and eventually accelerated during the Renaissance. In a similar fashion, knowledge about the comparative effectiveness of drugs to treat type 2 diabetes is finally beginning to emerge from 40 years of stagnation. This period of darkness and the current reawakening provide critically important lessons for contemporary medicine about the use of surrogate end points in drug development, regulatory oversight, and the hazards associated with reliance on commercial funding for pivotal clinical trials. OK, that’s the standard Lehman rant about diabetes trials. But it wasn’t written by me: there should be quotation marks around those opening sentences, which were actually written by Steve Nissen. That’s slightly ironic, given how much commercial funding he has received for conducting pivotal trials: but his editorial is still well worth reading. He is commenting on a large cohort study which compares the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death. It’s nothing so ground-breaking as a randomized trial, and it simply confirms that use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death, of about 20%. It doesn’t tell us if metformin is beneficial, or sulfonylureas are harmful, or a bit of both. And these drug classes appeared half a century ago…
November 12th, 2012
Nine Italian Cardiologists Arrested in Broad Investigation of Research Fraud and Misconduct
Larry Husten, PHD
Nine Italian cardiologists have been arrested as part of a broad investigation into serious medical misconduct at Modena Hospital, according to multiple reports in the Italian media. The investigation encompasses at least 67 other individuals and a dozen medical equipment companies, including 6 foreign companies. The charges include conspiracy, fraud, embezzlement, bribery, forgery, and performing unauthorized clinical trials. Several news reports mentioned that stents and angioplasty balloons were involved.
According to one Italian website, the investigation started in 2011 in response to allegations by a group, Amici del Cuore (Friends of the Heart), that patients at the Modena Hospital (Policlinico di Modena) received treatments and procedures as part of unauthorized experiments. In some cases the procedures may have resulted in fatal outcomes. The accused physicians “performed experimental tests without making it known to patients for the sole purpose of writing about these trials in specialized magazines collecting money through bogus non-profit organization,” the website reported. [All translations in this story taken from Google Translate.]
“We wanted to ask questions about certain procedures that went far beyond the standard ones, and that seemed unusual to us,” the president of Friends of the Heart, Professor Giovanni Spinella, told Il Salvagente. “We were aware that invasive procedures were performed, often on peripheral organs, and sometimes had little to do [with] the heart. And unfortunately had caused discomfort and damage to several patients.”
Another Italian site quoted a police official who called it “a major operation” and said the accused “committed human clinical trials without authorization and installed medical devices and equipment defective in patients unaware of being subjected to an experimental treatment.” The accused physicians then “created false medical records to cover medical errors.” The Italian media said the investigation included recordings of telephone conversations between the suspects. The Italian police named the operation camici sporchi (“dirty gowns”).
The most prominent person arrested was Maria Grazia Modena, the chief of cardiology at Modena Hospital and a former president of the Italian Society of Cardiology. (Grazia Modena was the subject of a profile in Circulation European Perspectives (PDF) in 2007.) Modena, 60 years old, was trained partly at New York University and the Mayo Clinic. The second main focus of the investigation appears to be the head of the catheterization laboratory at the hospital, Giuseppe Sangiorgi. According to news reports, he is the only arrested physician who is still in jail.
Here are the names of the nine physicians:
- Maria Grazia Modena, chief of cardiology
- Giuseppe Sangiorgi, head of the catheterization laboratory
- Luigi Vincenzo Politi
- April Alexander
- Simona Lambertini
- Giuseppe Biondi Zoccai
- Fabrizio Clement
- Alessandro Mauriello
- Andrea Amato
November 7th, 2012
Statins Use Linked to Reduction in Cancer Mortality
Larry Husten, PHD
A large new study raises the possibility that statin use may lead to a decline in cancer mortality. Researchers in Denmark used health data from the entire population of the country and analyzed the information from nearly 300,000 patients who were diagnosed with cancer between 1995 and 2007. The authors note that the relationship is biologically plausible, since cholesterol synthesis is required for cell proliferation and other critical cellular functions.
In their paper, published in the New England Journal of Medicine, the researchers compared 18,721 cancer patients who were statin users prior to their diagnosis with 277,204 who had never used statins. Here are the adjusted hazard ratios for statin users:
- All-cause mortality: 0.85 (0.83-0.87)
- Death from cancer: 0.85 (0.82-0.87)
A similar and consistent pattern was noted for different types of cancer, although these differences did not always achieve statistical significance. No dose-response relationship was observed in the study.
In an accompanying editorial, Neil Caporaso notes that despite the considerable strengths of the study, which used data from the entire country of Denmark, the researchers were nevertheless unable to account for residual confouding differences between statin users and nonusers. The “consistent and substantial declines in mortality across diverse cancers” need to be interpreted with caution, he wrote. Caporaso suggests a variety of different research directions for further study of the important question of the relationship between statins and cancer.
