October 1st, 2013
Long-Term Study Results Offer Broad Perspective on Hormone Therapy for Menopausal Women
Larry Husten, PHD
More than a decade ago, the NHLBI’s Women’s Health Initiative trials overturned the conventional wisdom that hormone therapy (HT) for menopausal women helped protect women from a broad spectrum of chronic diseases, including cardiovascular disease. The findings caused dramatic reductions in the use of HT but important questions remained, many involving the age or time since menopause of women taking HT. Now a report published in JAMA provides for the first time a comprehensive overview of the risks and benefits of HT.
“Overall,” the authors state, “the WHI findings suggest that hormone therapy has a harmful effect on CHD risk among older women, whereas the results in younger women remain inconclusive.”
In the WHI, more than 16,000 women with an intact uterus were randomized to the combination of estrogen and progestin or placebo (median length of treatment, 5.6 years). More than 10,000 women with a prior hysterectomy were randomized to estrogen alone or placebo (median length of treatment, 7.2 years). The new report contains data on an additional 6 to 8 years of follow-up.
Women randomized to estrogen and progestin had significantly elevated risks for coronary heart disease, breast cancer, stroke, pulmonary embolism, dementia (in women aged 65 years and older), gallbladder disease, and urinary incontinence. On the other hand, they were at reduced risk for hip fractures, diabetes, and vasomotor symptoms. After discontinuation of therapy, most of the effects, both positive and negative, were no longer apparent, though a small increase in breast cancer risk remained.
For women who received estrogen alone, the findings were less certain. Estrogen therapy in this group was associated with an increased risk for stroke and venous thrombosis, and a lowered risk for hip and total fractures. After discontinuation of therapy, most of the effects were no longer evident. The investigators were surprised by — and at a loss to explain — a small, nonsignificant drop in breast cancer; following discontinuation of estrogen therapy, this decrease achieved statistical significance. Women under the age of 60 in this group also had small but significant reductions in all-cause mortality and myocardial infarction.
The authors wrote:
“Even though hormone therapy may be a reasonable option for management of moderate to severe menopausal symptoms among generally healthy women during early menopause, the risks associated with hormone therapy, in conjunction with the multiple testing limitations attending subgroup analyses, preclude a recommendation in support of CEE use for disease prevention even among younger women. Current findings also suggest caution when considering hormone therapy treatment in older age groups, even in the presence of persistent vasomotor symptoms, given the high risk of coronary heart disease and other outcomes associated with hormone therapy use in this setting.”
In a press release, the NHLBI’s Jacques Rossouw warned about the long-term use of estrogen in younger women:
“While the risk versus benefits profile for estrogen alone is positive for younger women, it’s important to note that these data only pertain to the short-term use of hormone therapy. There are no reliable data on the risks or benefits of long-term hormone therapy use for the prevention of chronic diseases.”
In the same NHLBI press release, the principal investigator for the WHI, JoAnn Manson, said:
“The combination of the six to seven years of intervention combined with the extended post-intervention follow-up make these hormone therapy medications among the best studied medications in medical history. There are very few other treatments with this much information about the balance of benefits and risks over such a long period of time that include such a long post-intervention phase. The ultimate goal of this paper and the analysis is to help women and their health care providers make informed decisions.”
October 1st, 2013
ACS Symptoms in Young Patients: Be Aware of Sex Differences
Louise Pilote, MD, MPH, PhD
CardioExchange’s Editor-in-Chief, Harlan Krumholz, interviewed author Louise Pilote about the GENESIS PRAXY research group’s JAMA: Internal Medicine study, which examined sex differences in acute coronary syndrome (ACS) presentation and the associations between sex, sociodemographic, gender identity, psychosocial, and clinical factors, markers of coronary disease severity, and absence of chest pain in young patients with ACS. The researchers found that chest pain was the most common ACS symptom in both sexes. Women were more likely to present without chest pain than men, however, the absence of chest pain was not associated with markers of coronary disease severity.
Krumholz: You find that chest pain is a common presentation for young women with acute myocardial infarction. Why do you think that your findings are so different from the NRMI study published in JAMA?
Pilote: The NRMI study also found that chest pain was common among women, but the NRMI obtained data on chest pain symptoms from chart review. PRAXY obtained data on many symptoms at presentation from a patient questionnaire.
NRMI ended data collection in 2006. PRAXY is current. Perhaps women today are more aware of symptoms and recognize and report chest pain as a heart attack symptom.
Krumholz: You say that “Strategies that explicitly incorporate assessment of common non-chest pain symptoms need to be evaluated.” What kind of strategies do you mean?
Pilote: Education strategies for high-risk young women must help them to recognize their risk of ACS. Also, the evaluation of triage strategies in the ER that would require EKG and biomarker testing in high-risk young women who present with non-chest pain symptoms.
Krumholz: Are there important implications of your study for clinicians?
Pilote: Young women do get ACS. Education and risk-factor reduction must be a priority. Non-chest pain symptoms in high-risk women must be evaluated.
September 30th, 2013
Selections from Richard Lehman’s Literature Review: September 30th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection 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.
NEJM 26 Sep 2013 Vol 369
Dabigatran vs. Warfarin in Patients with Mechanical Heart Valves (pg. 1206): One of the few genuinely promising advances I’ve been able to track in the journals over fifteen years has been the arrival of fixed dose oral anticoagulants. My, how the drug companies have scrambled to conquer this immense market! Boehringer-Ingelheim managed to score with dabigatran for atrial fibrillation in the RE-LY trial, though doubts remain, and the cost is prohibitive for routine use. The authors of this paper describe how this success then spurred them to set up the phase 2 trial RE-ALIGN trial in 39 centres across 10 countries to see if they could find a new market in people with mechanical heart valves. In the chosen settings, patients in the comparator group receiving warfarin were in the target INR range just 50% of the time. But despite this obvious source of gross bias, dabigatran failed to show any added benefit, and showed an excess of bleeding. Goodbye dabigatran for mechanical valve patients.
JAMA Intern Med 23 Sep 2013 Vol 173
Echocardiographic Screening of the General Population and Long-term Survival (pg. 1592): I was once interested in population echographic screening for systolic dysfunction and valvular disease (I was a naïve 45-year old back then), but I gradually realised the error of my ways. My interest moved to BNP screening in high risk groups—but that is another story, and another error. Here are the long-term results from 6861 middle-aged participants from the population-based Tromsø Study in Norway who were randomised 15 years ago to have echocardiography or not. “During 15 follow-up years, 880 persons (26.9%) in the screening group and 989 persons (27.6%) in the control group died (hazard ratio, 0.97; 95% CI, 0.89-1.06). No significant differences between the groups were observed in the secondary outcome measures (sudden death, mortality from any heart disease, or incidence of fatal and nonfatal myocardial infarction and stroke).”
Use of Antihypertensive Medications and Breast Cancer Risk Among Women Ages 55 to 74 (pg. 1629): Drugs to lower blood pressure in middle-aged people typically have numbers-needed-to-treat of several hundred to prevent an adverse cardiovascular event within 10 years. So any drug you use to lower blood pressure must (a) be proved to reduce CV events and (b) be proved to be free of long-term harms. Millions of women across the world use calcium channel blockers to reduce blood pressure, and this case-control study from the Seattle–Puget Sound metropolitan area raises the unwelcome possibility that this doubles their chance of getting breast cancer over a 10 year period, regardless of the odipine, adipine or edipine used. Someone urgently needs to do a massive data trawl of the UK CPRD, to settle the matter within weeks.
September 30th, 2013
Nesiritide Does Not Increase Diuresis in ADHF Patients
Stephen Gottlieb, MD
In a new analysis of data from the ASCEND-HF trial, investigators found that nesiritide did not increase urine output in patients with acute decompensated heart failure (ADHF). CardioExchange Editor-in-Chief Harlan Krumholz interviews lead investigator Stephen Gottlieb about the study, which was recently published in the Journal of the American College of Cardiology.
Krumholz: You found that nesiritide did not increase urine output. Many clinicians would have bet that it did increase diuresis on the basis of their clinical experience. Did the result surprise you?
Gottlieb: In my clinical experience, I have not seen improved diuresis with nesiritide, but certainly many clinicians believe that it is very effective. I wonder whether this reflects treatment of different patients. Perhaps severe chronic HF patients don’t respond, while patients with acute HF or rapid decrease in brain natriuretic peptide (e.g., after total artificial heart implant) do respond. This may be worth investigating, but one would want to know if patients who did respond to nesiritide derived benefit from it (or would they also respond to conventional diuretics).
Krumholz: What does ASCEND-HF tell us about the importance of doing outcomes trials to test interventions that are approved based on surrogate endpoints? Did it change your thoughts at all?
Gottlieb: I believe that ASCEND-HF answered many clinically important outcomes and, thus, was an important study. The results of ASCEND-HF showed no improvement in what doctors and patients care about — mortality, hospitalizations, renal function, and urine output. Whether FDA approval for short-term dyspnea improvement is appropriate is a different question that ASCEND-HF cannot answer.
Krumholz: What does your study tell clinicians about their care of patients with HF? Should we be using diuretics in higher doses for patients with ADHF?
Gottlieb: Not all HF patients need diuresis, but in those who do (probably a majority of those hospitalized) I believe that reluctance to use high doses of furosemide has limited success in diuresis. This is consistent with the excellent diuresis seen in the aggressive protocols of CARESS.
September 27th, 2013
Saying Sorry May Not Be Good Enough for Novartis
Larry Husten, PHD
Novartis has issued a formal apology over misconduct relating to valsartan (Diovan) research in Japan, but that apology does not appear likely to satisfy the Japanese Health, Labor and Welfare Ministry, which plans to fully investigate the company’s role in the scandal. If necessary, ministry officials are prepared to raid the company’s offices in Japan.
A Novartis official apologized to the Japanese public for the apparent manipulation of data. David Epstein, the head of the pharmaceutical division at Novartis, met with the Japanese health minister. “We express our deep regret for the concern that the issue has brought to patients, to the medical society as well as the ministry,” Epstein was quoted by Reuters after the meeting. He said the company was “willing to work with” Japanese investigators and will “take additional actions and potential sanctions in order to bring the issue to a good conclusion.”
Epstein laid the blame for the scandal on a former Novartis employee who participated in the trials and acted “way beyond what we consider appropriate.” As previously reported here, that employee, Nobuo Shirahashi, worked on both the Kyoto and Jikei Heart Studies but did not disclose that he was actually an employee of Novartis. In response to the accusations, Shirahashi told an expert panel assembled by the Japanese ministry that he had no involvement in any data manipulation, according to a report in The Mainichi. The expert panel found that Shirahashi was involved not only in the previously reported studies from the Jikei University School of Medicine and the Kyoto Prefectural University of Medicine, but was also involved in valsartan research conducted at Shiga University of Medical Science, Chiba University, and Nagoya University.
Two other once-prominent Japanese cardiologists, Seibu Mochizuki, who was the principal investigator of the Jikei Heart Study, and Hiroaki Matsubara, the principal investigator of the Kyoto Heart Study, also denied any wrongdoing to the expert panel. They placed the blame for any misdonduct on Shirahashi.
The expert panel is not just looking at individual responsibility. According to an AFP news report, the panel has concluded that Novartis “should be held responsible for studies at various universities that used manipulated data on a popular blood pressure drug.” The panel is scheduled to complete its preliminary investigation on September 30, after which it will launch a full-scale investigation. According to The Mainichi:
The Pharmaceutical Affairs Act forbids companies from taking out ads in which they intentionally use false or exaggerated expressions to have many people use their drugs and medicines. Violators of the law could face up to two years in prison or a fine of up to 2 million yen. The health ministry could impose administrative punishments such as revoking manufacturing and distribution licenses and impose business-suspension orders on pharmaceutical companies for violating the law.”
Novartis issued the following statement in response to reports of the Japanese investigation:
On September 26, David Epstein, Division Head of Novartis Pharmaceuticals, met with Mr. Norihisa Tamura, the Minister of Health, Labor and Welfare of Japan following an invitation by the Minister. Novartis expressed its regret for the inconvenience caused by the valsartan investigator initiated trails (IITs) in Japan and expressed its continued willingness to address and overcome this issue in Japan.
Novartis is aware of recent media reports concerning the investigation by the MHLW into the Japanese IITs. To date, the MHLW has not published the interim report related to their investigation. Novartis will not speculate on outcomes until we receive official notification from the MHLW.
Novartis takes allegations of conflict of interest and reliability of data very seriously. In April, we launched an investigation using third party experts to investigate these allegations. The investigation has now been completed and confirmed there was an undisclosed COI but did not discover any evidence of willful manipulation or falsification of data in these studies.
Novartis Pharma K.K. (NPKK), Japan has taken preventive and corrective measures to address the causes identified in the third party investigation, including redesigning the standard operating procedures (SOP) for IITs and retraining employees on Conflict of Interest guidelines and process for IITs.
Novartis remains committed to conducting clinical research in Japan and bringing new medicines to patients in Japan, in accordance with applicable laws and regulations while following the highest standards of ethical business conduct in all aspects of our work.”
September 27th, 2013
Higher Physician Volume Leads to Lower Mortality in HF
Karen Joynt, MD, MPH
CardioExchange’s Editor-in-Chief, Harlan Krumholz, interviewed lead author Karen Joynt about her Circulation: Heart Failure study, which examined the relationship between physician volume, clinical outcomes, and costs among patients with heart failure (HF). The researchers found that high physician volume was associated with lower mortality, and that the association was particularly strong in lower-volume hospitals and among noncardiologist physicians.
Krumholz: You showed that physician volume is associated with lower mortality for HF, especially in low-volume institutions. Given that most patients see many doctors, how did you determine the volume of patients for each doctor?
Joynt: For this study, we only looked at the attending of record for each patient. If the attending of record was a physician that saw only two Medicare HF patients in 2009, then the patient was classified into the “low-volume” group. We didn’t evaluate whether or not there were additional physicians consulting on that patient’s care.
Krumholz: Are you confident that you were able to control for differences in the types of patients that seen by high- and low-volume doctors?
Joynt: Controlling for differences in patient factors is always tricky when using administrative data, because we just don’t have clinical variables like ejection fraction or creatinine that would let us precisely estimate each patient’s risk. We think the models, particularly for mortality, are reasonably good, but they are certainly not perfect. Intuitively, it seems likely that high-volume physicians see the sickest patients – people refer the most challenging patients to the “experts” rather than the other way around, so if anything this would have biased us against finding a relationship, but it’s hard to know for sure.
Krumholz: Why do you think that the relationship was stronger in low-volume institutions?
Joynt: I suspect that the volume-outcome relationship was strongest in low-volume institutions because the care of an HF patient depends not only on the physician, but on the whole team. The nurses, physical therapists, nutritionists, and social workers play an absolutely critical role in HF patients’ hospitalizations. A low-volume institution may have fewer systems in place, or less-uniform care, and the effect of a physician’s experience may carry more weight. At a high-volume institution, there are a lot more people who have a great deal of expertise in caring for HF patients, so even if you have a relatively low-volume physician, you still have a lot of collective experience surrounding that patient. Additionally, centers that have a lot of HF patients are more likely to have care protocols, discharge protocols, etc., that may improve outcomes even independent of the clinicians involved in the patients’ care – the “systems” effect.
Krumholz: Is there a message here for patients?
Joynt: The main take-away for patients is that both physician and hospital volume matter. If you have HF, it may be worth it to seek out a clinician who treats a lot of HF patients, or perhaps a center that treats a lot of HF patients. It’s also worth stating that it’s not realistic for all patients to see high-volume HF doctors in person if they happen to live someplace that is geographically isolated – but it doesn’t mean they shouldn’t have access to experienced specialists. We need to do a better job of developing partnerships and technologies that allow for things like telemedicine, or remote consultation, to bring the experts to the patients rather than the other way around.
September 26th, 2013
Increase In Deaths Linked To First-Line Treatment With Sulfonylureas
Larry Husten, PHD
First-line treatment with sulfonylureas instead of metformin in people with type 2 diabetes is associated with a significantly elevated risk of death, according to results from an observational study presented at the European Association for the Study of Diabetes (EASD) meeting in Barcelona.
Although guidelines do not recommend the use of sulfonylureas for first-line treatment, the drugs are still commonly prescribed this way in many countries. CJ Currie, an epidemiologist at Cardiff University in the UK, said that 7% of diabetics in the UK receive first-line treatment with sulfonylureas. He presented data from the Clinical Practice Research Datalink (CPRD), which includes 10% of primary care patients in the UK. Between 2000 and 2012, 76,811 patients with type 2 diabetes began glucose-lowering treatment with metformin, while 15,687 began treatment with sulfonylureas (which include glipizide, glyburide, and glimepiride).
After adjusting for baseline differences, mortality was 58% higher in the sulfonylurea group. (The crude rates were 44.6 deaths per 1000 patient-years in the sulfonylurea group versus 13.6 in the metformin group.) A significant mortality increase in the sulfonylurea group was found in additional direct-matched and propensity-matched analyses.
The authors acknowledged that while “residual confounding and confounding by indication may remain, this study indicates that treatment with first-line monotherapy with sulfonylureas should be reconsidered.” At a news conference in Barcelona, Currie said that because this is an observational study it is “not a smoking gun,” but he strongly recommended that regulatory authorities take a close look at the issue.
At the press conference Currie also presented data from an analysis of second-line therapy, comparing the combination of metformin and sulfonylureas, in 34,000 patients, with the combination of metformin and DPP-4 inhibitors, or glistens, in 8000 patients. Overall there were 1200 deaths. There were 16.0 deaths per 1000 patient-years in the metformin-sulfonylurea group versus 7.3 for the metformin-DPP-4 group. After adjusting for baseline characteristics Currie said there was a significant 35% increase in death in the metformin-sulfonylurea group.
September 25th, 2013
Is It Safe to Treat Acute Pulmonary Embolism in an Outpatient Setting?
Christopher Kabrhel, MD MPH
CardioExchange’s John Ryan interviews Christopher Kabrhel about his research group’s study of the factors associated with clinical deterioration and the need for hospital-based interventions after an acute pulmonary embolism (PE). The study was presented in June at the 24th congress of the International Society on Thrombosis and Haemostasis.
THE STUDY
From October 2008 through December 2011, researchers prospectively enrolled 298 consecutive patients with radiographically confirmed PE at the emergency department (ED) of a U.S. tertiary care hospital. One third of patients experienced serious clinical deterioration or required a major hospital-based intervention (the primary outcome) within the first 5 days after PE diagnosis. The median length of hospital stay was 3 days. The mortality rate was 1% within 5 days and 4% within 30 days.
In multivariable analyses, factors significantly associated with the primary outcome were abnormal vital signs, coronary artery disease, cerebrovascular disease, deep-vein thrombosis (DVT), and right-heart strain on echocardiogram; factors significantly associated with 30-day all-cause mortality were malignancy and chronic lung disease.
THE INTERVIEW
Ryan: How do these findings change your practice?
Kabrhel: In the United States, nearly all patients with PE are hospitalized for anticoagulation and monitoring. We know that anticoagulation can be initiated and coordinated without hospitalization. This is the current standard for DVT, and novel anticoagulants make this even easier. The main justification for admission is monitoring.
In our study, 67% of patients diagnosed with PE in the ED suffered no clinical deterioration and required no hospital-based intervention during hospitalization. We defined clinical deterioration very broadly to capture a wide spectrum of events that might justify hospitalization. For example, simply requiring more than 2 liters of nasal cannula oxygen was considered deterioration. Similarly, hypotension was considered deterioration even if it did not require treatment. Given that the majority of patients with PE did not clinically deteriorate and did not require any hospital-based intervention, hospitalizing patients with low-risk PE for monitoring seems unnecessary.
Our data support the current trend toward treating low-risk patients with PE as outpatients and show that the proportion who might be appropriate for outpatient treatment is quite large. However, we also found that existing clinical prediction instruments were only moderately sensitive for identifying patients who clinically deteriorate. Clinicians should exercise caution in using these rules as the basis for disposition decisions.
Ryan: What do you advocate including in the PE guidelines — or what further research needs to be done first?
Kabrhel: Outpatient treatment of PE is reasonable and may be appropriate for a large number of patients. However, further research is needed before we establish clinical guidelines. Clinical decision instruments should be designed and validated using outcomes that reflect the decision they are designed to support. Logically, a decision rule designed to help physicians decide which patients with PE benefit from hospitalization (or conversely, which patients can be treated as outpatients) should be studied relative to events that occur during a typical hospitalization for PE. We took that approach in our study.
Ryan: As you say, we need better rules to decide which patients with PE require hospitalization. What’s the best way to currently identify who will do well?
Kabrhel: We found that certain clinical factors (abnormal vital signs, right-heart strain on echocardiogram, residual DVT, and a history of cardiovascular disease) were associated with clinical deterioration in the 5 days after an acute PE. These factors can help clinicians decide which patients require hospitalization. In settings where an echocardiogram is difficult to obtain, biomarkers (e.g., troponin, brain-type natriuretic peptide) or ECG changes may be useful surrogates. Of course, clinicians should also consider other factors, such as the social circumstances that affect a patient’s ability to adhere to outpatient therapy.
JOIN THE DISCUSSION
Does this study influence your judgment about whether a substantial percentage of patients with acute PE can be treated safely in an outpatient setting?
September 24th, 2013
Study Raises Questions About Digoxin Use Today
Larry Husten, PHD
Digoxin is one of the oldest medicines in the cardiovascular arsenal. When William Withering identified it as the active ingredient in the foxglove plant more than 200 years ago, he was only codifying a longstanding folk remedy for heart failure, or “dropsy” as it was known then.
Digoxin fully entered the modern era with the publication of the DIG trial in 1997. The trial found that digoxin reduced hospitalization for heart failure but did not have an impact on mortality. On the basis of the trial, digoxin received recommendations in U.S. and European guidelines for use in patients with systolic heart failure who remain symptomatic despite optimal therapy. However, the epidemiology and treatment of heart failure have evolved considerably since then. Now, the authors of a new study, supported by an accompanying editorial, say that these recommendations need to be reconsidered.
In the study, published in Circulation: Cardiovascular Quality and Outcomes, James Freeman and colleagues followed 2891 patients with newly diagnosed systolic heart failure, 18% of whom received digoxin. After 2.5 years, the digoxin users had a higher rate of death and hospitalization for heart failure:
- Death: 14.2 versus 11.3 per 100 person-years
- HF hospitalization: 28.2 versus 24.4 per 100 person-years
After adjustment for other factors, the increase in mortality — but not the increase in hospitalization — remained significant:
- Digoxin hazard ratio for mortality: 1.72, CI 1.25–2.36
- Digoxin hazard ratio for hospitalization: 1.05, CI 0.82–1.34
The overall findings were consistent for both men and women and for beta-blocker users and nonusers.
The authors acknowledged that because they performed an observational study, they were unable to demonstrate a direct cause-and-effect relationship with digoxin. However, they pointed out that since the DIG trial, “substantial improvements in HF treatment have occurred,” including increased use of beta-blockers, ACE inhibitors, ARBs, and aldosterone antagonists, which “may substantially modify the independent effect of digoxin on death and HF hospitalization.” They write that their “community-based systolic HF cohort is more likely to represent patients with systolic HF in the modern era with regard to pathogenesis and treatment patterns.” They recommend that the use of digoxin for systolic heart failure should be “re-evaluated.”
In an accompanying editorial, Lionel Opie writes that the new study “is of considerable importance” because the evidence base for the current use of digoxin is “highly unsatisfactory.” He agrees with the study authors that it is time to “seriously question” the U.S. and European guidelines that support the current use of digoxin.
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