CardioExchange Archive

PFO Closure Trial Misses Primary Endpoint:  The CLOSURE 1 trial, which was designed to test the efficacy of PFO closure in preventing recurrent strokes and TIAs, failed to meet its primary endpoint, according to a press release from the trial’s sponsor, NMT Medical.  The primary endpoint of the trial, which was designed to compare PFO closure to medical therapy in 900 patients with documented stroke or TIA who had a PFO, was the two-year rate of stroke or TIA, as well as all-cause mortality for the first 30 days of follow-up or hospital discharge, whichever is longer, and neurological mortality from >31 days of follow-up.

New Concerns Raised Over Insulin Glargine and Taspoglutide: A study published online in Diabetes Care found an increase in the risk of cancer associated with higher doses of insulin glargine (Lantus, Sanofi). A Sanofi representative told Bloomberg News that the study was too small to be reliable. The study appears almost exactly one year after studies in Europe first raised cancer concerns over the drug.

The development of taspoglutide, which had been the subject of a series of promising press releases from its manufacturer, Roche, will now be delayed for at least 12-18 months. In a press release, Roche said it had found a higher than expected rate of hypersensitivity in phase-3 studies and that it would implement a risk-mitigation plan.
INTERSTROKE: Accounting for Stroke: Ten risk factors appear to account for 90% of the risk of stroke, according to INTERSTROKE, a large study presented at the World Congress of Cardiology in Beijing and published online in the Lancet. The study compared 3000 stroke patients (78% with ischemic stroke) in 22 countries and identified hypertension as the most important risk factor, associated with one-third the risk for all strokes. The other risk factors were smoking, waist-to-hip ratio, diet, physical activity, lipids, diabetes, alcohol intake, stress and depression, and cardiac disorders. For intracerebral hemorrhage, hypertension, smoking, waist-to-hip ratio, diet, and alcohol were independently significant.

With the exception of cardiac disorders, the risk factors are the same as those found in the related INTERHEART study of risk factors for MI, though the relative importance of the factors differed between the studies: lipids and not hypertension were the most important risk factor in INTERHEART. The authors conclude that “targeted interventions that reduce blood pressure and smoking, and promote physical activity and a healthy diet, could substantially reduce the global burden of stroke.”

Industry Employees May Not Be Allowed to Speak at the AHA: Industry employees may no longer be allowed to speak at the AHA scientific sessions and other CME-accredited events, according to an article by John Fauber in the Milwaukee Journal Sentinel. The ruling by the the Accreditation Council for Continuing Medical Education (ACCME) is being appealed by the AHA. The ruling was harshly condemned by NIH Director Francis Collins and other biomedical leaders.

New-Generation Stent Tested: In the Resolute All Comers Trial, Patrick Serruys and colleagues randomized 2,292 PCI patients to either the Resolute zotarolimus-eluting stent or the Xience V everolimus-eluting stent. At 12 months, the rate of target lesion failure was 8.2% in the Resolute arm and 8.3% in the Xience V arm, thereby demonstrating noninferiority of the new Resolute stent (P<0.001 for noninferiority). There were no significant differences in death from cardiac causes, MI, or revascularization between the two groups. Stent thrombosis occurred in 2.3% of the Resolute group compared to 1.5% of the Xience V group (P=0.17).

A key feature of the trial is that it enrolled many patients excluded from previous stent trials, such as those with coexisting illnesses, acute MI, and multivessel disease. In their report in the New England Journal of Medicine, the investigators conclude that “the new-generation zotarolimus-eluting stent was found to be as safe and effective as the everolimus-eluting stent in a group of patients for whom the procedure was considered to be predominantly off-label.”

BMS Versus DES for STEMI: Kaltoft and colleagues randomized 626 STEMI patients to a drug-eluting or a bare-metal stent. At 3 years, the rate of major adverse cardiac events was 11.5% in the DES group versus 18.2% in the BMS group (P=0.02). Although there was no difference in all-cause mortality, there was a significant difference in cardiac death (6.1% for DES vs. 1.9% for BMS, P=0.01). In their report in the Journal of the American College of Cardiology, the investigators observe that “the very low cardiac mortality rate in our BMS group is hard to interpret, and the excess cardiac DES mortality should be interpreted accordingly and might have occurred by chance.”

Jaffri and colleagues found a significant inverse association between HDL and the risk of cancer in a meta-analysis of 24 trials that included more than 600,000 person-years of follow-up and 8,185 cancer cases. In their paper in the Journal of the American College of Cardiology, they report a dose-response relationship in which each 10-mg/dl increase in HDL was associated with a 36% lower rate of cancer. The association remained significant after adjustment for other baseline factors, including LDL, age, BMI, diabetes, sex, and smoking status.

“This finding is important because it builds on previous studies demonstrating that low levels of LDL or bad cholesterol and total cholesterol are associated with increased rates of cancer,” said Richard Karas, the senior author of the study, in a press release from the ACC.

In an accompanying editorial comment, Jennifer Robinson discusses the strengths and weaknesses of the finding. Among the strengths she cites the lack of evidence for reverse causality (in which cancer would be the cause of the low HDL levels), the dose-response relationship, and a biologically plausible explanation for the association. On the other hand, she cites several alternate explanations, in which low HDL might be “simply a marker for smoking, obesity, inflammation, or hyperinsulinemia” or other dietary and lifestyle factors. She also observes that “currently there is insufficient evidence to conclude that pharmacologically increasing HDL-C per se reduces cardiovascular events.”

Although “the most important criteria for causality have not yet been met,” Robinson writes in her conclusion:

“Clearly, individuals with low HDL-C may experience particular benefit from lifestyle recommendations to quit smoking, improve diet, engage in regular physical activity, and control weight. Regardless of the effects on HDL-C, healthy lifestyle habits have a significant impact on the prevention of most of the chronic diseases associated with aging.”

Angiotensin-receptor blockers have been the subject of recent critical scrutiny. Last week, the FDA announced it was conducting a safety review of olmesartan. Over the weekend, the Lancet Oncology published a meta-analysis that found a small but statistically significant increase in the risk of developing new cancers in subjects taking ARBs.

The authors of the Lancet Oncology paper, led by Ilke Sipahi of Case Western Reserve University, acknowledged several important limitations of their analysis. As most of the available cancer data was for one ARB, telmisartan, it was impossible to make conclusions about individual ARBs. There was no significant difference in cancer deaths or in the incidence of individual cancers, with the exception of lung cancer, where a small but significant difference was observed.

Steve Nissen 
In an accompanying comment, Steve Nissen wrote that the meta-analysis “is disturbing and provocative, raising crucial drug safety questions for practitioners and the regulatory community. Are [ARBs] associated with increased risk of incident malignancies? Should we be concerned about all ARBs or a single drug, telmisartan? How can this uncertainty best be resolved? What actions should practitioners take while this concern undergoes further examination and analysis?”

Nissen called on regulatory authorities to initiate a thorough review of “the possible association between ARB use and cancer, and promptly report their findings.” Until then, he writes, “we should use ARBs, particularly telmisartan, with greater caution. These drugs are often overprescribed, as a result of aggressive marketing and in the absence of evidence that they are better than angiotensin-converting enzyme (ACE) inhibitors. ARBs can be reserved for patients with intolerance to ACE inhibitors. More selective use of ARBs will also save money for healthcare systems, since nearly all ARBs are proprietary and ACE inhibitors are generic.”

CardioExchange asked Clyde Yancy, the president of the AHA, and Franz Messerli, the director of the Hypertension Program at St. Luke’s-Roosevelt Hospital, to comment on the FDA safety review and the Lancet Oncology meta-analysis. Here are their remarks:


Clyde Yancy
To begin, we must quickly acknowledge that ARBs as a drug class have proven, evidence-based indications to reduce the incidence of stroke, improve outcomes post-MI, improve outcomes in heart failure, and retard the progression of chronic kidney disease. Additionally, these drugs are especially effective in ACE-intolerant patients either due to intractable cough or a prior history of angioedema. Thus, the medical community has appropriate high regard for the benefits of ARBs.

What is notable in this FDA MedWatch alert is the patient cohort being considered; that this question has been raised in a diabetic patient population is of interest. The recent ACCORD BP trial done in diabetics raised the very real concern that the extent of blood pressure lowering is an issue. In diabetic patients, the lower the blood pressure, the better … to a certain point, after which risk does emerge. What will need to be done very carefully in this FDA analysis is a careful process of review that controls for the extent of BP control. If the nadir of BP control in those treated with olmesartan is below 119 mm Hg, real risk may have been possible. Beyond that, we must always respect the play of chance in any post hoc analysis from data not prospectively acquired to address the question being pursued in the analysis.

The Lancet Oncology raises yet another question about the safety of ARBs. In a meta-analysis done by investigators at Case Western, a review of >60,000 patients exposed to one of three ARBs in five clinical trials with very disparate patient populations revealed a very modest but statistically significant increased incidence of cancer, particularly lung cancer. The incidence of death due to cancer was not different, and the risk was quite small. I have spoken with the investigators and agree with them that this finding requires very cautious interpretation. Despite a careful analysis, a statistical quirk may still be the only relevant explanation. Moreover, true biological plausibility is lacking for this observation. At best this is a question, and a question only, to be addressed in new datasets or by evaluating even more data, both published and unpublished. In the accompanying editorial by Steve Nissen, he calls for more extensive data analysis of existing datasets. Drug safety is of paramount importance to all of us, but drug paranoia must be avoided as the evidence supporting both benefit and safety is compelling for ARBs.

Overall then, ARBs are safe when used for appropriate indications and when used according to now well-refereed guidelines. Indiscriminate use of any drug should be discouraged, and the same can be said for ARBs. But no person taking these compounds at present should be hesitant about continuing therapy, and importantly any thought to discontinue therapy should be reviewed with the prescribing physician.

Franz Messerli
Ever since the use of reserpine was associated with an increased risk of breast cancer more than 50 years ago, the question of antihypertensive drugs and cancer has not come to rest. Over the past decades, beta-blockers have been associated with lung cancer, calcium blockers with cancer in general, thiazide diuretics with renal cell carcinoma and colon cancer. (Grossman, Messerli, et al. 2001. Review.) In most instances, the risk is small and not supported by biochemical, experimental, or epidemiological data. The relationship between reserpine and breast cancer is statistically significant but of little clinical concern because reserpine is no longer used. The relationship between diuretic therapy and renal cell carcinoma is supported by a variety of clinical, biochemical, and experimental data and remains of concern, particularly in women.  

Blockers of the renin angiotensin system have experienced a remarkably favorable record in this regard, ever since a retrospective study from Scotland (Lever et al. 1998) showed that the use of ACE inhibitors potentially protects against cancer. In most studies and meta-analyses, the risk of cancer with RAS blockers was either equal or lower than with their comparator, including placebo. Thus, the present study by Sipahi showing a modestly increased risk of new cancer diagnosis with ARBs is unexpected and certainly warrants scrutiny and further investigation. There is little, if any, biological plausibility that a drug exposure of only a few years would increase the risk of new cancer diagnosis. Cigarette smoking, which is one of the most powerful risk factors for lung cancer, will require 10 years or longer exposure to significantly increase lung cancer risk. Thus, it’s exceedingly unlikely that short-term drug exposure (as happens in clinical trials) of ARBs would have a clinically meaningful effect.

Unfortunately, blood pressure still remains uncontrolled in many patients and exposes them to the risk of having a heart attack or stroke. To get blood pressure to goal, we need to extensively use all available antihypertensive drug classes. The news that some of these antihypertensives potentially could cause cancer is alarming for patients who are on these drugs and could motivate them to abruptly discontinue treatment. While we cannot avoid — nor want to avoid — sharing this information with our patients, it should be done prudently.

ARBs are better tolerated than ACE inhibitors, which cause a dry cough in about 15% of all patients and much more rarely angioedema, which can be fatal. The risk of angioedema is particularly high in African-American patients, in whom ARBs therefore are often preferred. 

An apparent weakness is that the study was driven by one ARB alone — telmisartan. I do not know whether data obtained with telmisartan can be generalized to ARBs as a class. Time-to-event findings are not available, which are exceedingly important in carcinogenesis studies.

The FDA announced an ongoing safety review of olmesartan (Benicar). The agency said it “has not concluded that Benicar increases the risk of death” and advises patients and healthcare professionals that it “currently believes that the benefits of Benicar in patients with high blood pressure continue to outweigh its potential risks.” The review was prompted by unexpected findings in the ROADMAP and ORIENT clinical trials of an increased number of cardiovascular deaths in patients taking olmesartan compared to placebo.

Cardiac Embolism May Have Killed 13th Century Mummy: Italian researchers may have solved a 700-year-old medical mystery. It had previously been speculated that tuberculosis had been the cause of death of an 18- to 19-year-old girl who died in the 13th century and whose mummified remains have been preserved at the Santa Rosa monastery in Italy. But Ruggero D’Anastasio and colleagues found no evidence of chronic infectious disease. Instead, examination of the mummified chest and heart is consistent with Cantrell’s syndrome, and radiographic evidence of a mass between the apex of the left ventricle and the entry of the diverticulum suggests that the girl may have died of a cardiac embolism. The article appears in the Lancet.

Busy Summer at the FDA: In addition to the previously announced FDA advisory panel for the ticagrelor (Brilanta, AstraZeneca) NDA on July 28, the FDA will hold an extraordinary 2-day advisory panel to consider the fate of rosiglitazone (Avandia) on July 13 and 14. In addition, heartwire reports, but the FDA has not yet officially announced, that dabigatran (Pradax, Boehringer Ingelheim) will be reviewed on September 17. The FDA normally posts a detailed agenda, briefing materials, and the panel roster two days prior to the meeting.

Decline in MIs Observed Over Past Decade: Yeh and colleagues reviewed data from 46,000 hospitalizations for MI among more than 3 million people enrolled in the Kaiser Permanente Northern California system. In their paper in the New England Journal of Medicine, they report that from 1999 to 2008 the rate of MI decreased by 24%, resulting in a reduction from 274 cases to 208 cases per 100,000 person-years. The reduction in STEMI cases was even more marked, from 133 cases to 50 cases per 100,000 person-years. Thirty-day mortality was also reduced, which the authors say might have been driven by the drop in STEMI and the lower rate of death from non-STEMI.

In an accompanying perspective, JR Brown and GT O’Connor write that the reduction in MI may be due, in part, to greater use of statins, beta-blockers, ACE inhibitors, and angiotensin-receptor blockers. Because of adverse lifestyles and nutrition, however, the “rate of improvement has slowed down or stopped.” And, they observe, “as a nation, we are not making prevention a priority in our hospitals, clinics, schools, or communities.”

Smoke-Free Legislation Reduces MI Admissions in England: Michelle Sims and colleagues analyzed data on hospital admissions in England to examine the effect of smoke-free legislation on MI. Following implementation of the legislation in July 2007, emergency admissions for MI dropped significantly (by 2.4%) in the next year, resulting in 1,200 fewer admissions, according to the retrospective analysis appearing in the British Medical Journal. The authors conclude: “Given the large number of myocardial infarction events per year, even the relatively small reduction seen in England has important public health benefits.”

Danish Study Sheds Light on Cardiovascular Risk of NSAIDs: The cardiovascular safety of NSAIDs has been the subject of intense controversy. A new study from Denmark, appearing in Circulation: Cardiovascular Quality and Outcomes, may help clarify the cardiovascular risk of specific NSAIDs. Using national health and pharmacy databases, the Danish investigators identified more than 1 million people without illnesses requiring hospitalization within the previous 5 years who received prescriptions for NSAIDs. The researchers then found a dose-dependent risk of cardiovascular death in patients taking diclofenac and rofecoxib. Ibuprofen treatment was associated with an increased risk of stroke. By contrast, there was no excess risk associated with naproxen.

“Even though the frequency of these effects is quite low, they are still important,” said the study’s first author, Emil Loldrup Fosbol, in an AHA press release. “People should at a minimum be aware that this is a problem.” The authors expressed particular concern about diclofenac, noting that it is widely used throughout the world and is available in many countries as an over-the-counter medication.

Commenting for the AHA, Elliott Antman said the study provides a rare degree of completeness in calculating risks: “This is not information you can get in the U.S. because we just don’t have this ability to track individual records in the same way.”