October 26th, 2011
Danish Study Clarifies VTE Risk Associated with Newer Progestogens in Oral Contraceptives
Larry Husten, PHD
A large new study from Denmark provides the best evidence yet that third-generation oral contraceptives (OCs) containing drospirenone, desogestrel, or gestodene (sometimes used to treat dysmenorrhea) are associated with twice the risk for venous thromboembolism (VTE) as second-generation OCs containing levonorgestrel.
In a paper published in BMJ, Øjvind Lidegaard and colleagues analyzed data from national registries containing more than 8 million woman-years of observation, including 2847 confirmed VTE events.
Here are the relative risks for VTE with OCs when compared to no hormonal contraception (all OCs also contained 30-40 μg ethinyl estradiol):
- levonorgestrel: 2.9 (CI 2.2 – 3.8)
- desogestrel: 6.6 (5.6 – 7.8)
- gestodene: 6.2 (5.6 – 7.0)
- drospirenone: 6.4 (5.4 – 7.5)
Here are the relative risks with the newer OCs compared to those containing levonorgestrel, after adjustment for length of use:
- desogestrel: 2.2 (1.7 – 3.0)
- gestodene: 2.1 (1.6 – 2.8)
- drospirenone: 2.1 (1.6 – 2.8)
The authors calculated that to prevent one VTE event in 1 year, 2000 women would need to switch from an OC containing a newer progestogen to an OC containing levonorgestrel.
In an accompanying editorial, Philip Hannaford writes:
Although unpalatable to some, it is difficult not to conclude that combined oral contraceptives with desogestrel, gestodene, or drospirenone confer a higher risk of venous thromboembolism than those with levonorgestrel. Many clinicians will choose to minimise the risk by prescribing a combined oral contraceptive with levonorgestrel whenever possible. It is crucial, however, not to exaggerate the risk—oral contraceptives are remarkably safe and may confer important long term benefits in relation to cancer and mortality.
October 25th, 2011
Genetic and Clinical Factors Linked to Stent Thrombosis
Larry Husten, PHD
French researchers have identified several genetic and clinical factors independently tied to early stent thrombosis. Writing in the Journal of the American Medical Association, Guillaume Cayla and colleagues report on their case-control study comparing 123 patients with definite early stent thrombosis with 246 matched controls without stent thrombosis.
The researchers found three genes with variants that significantly and independently raised the risk for early stent thrombosis:
- CYP2C19
- ABCB1
- ITGB3
Independent clinical factors were:
- Acuteness of PCI
- Complex lesions
- LVEF <40%
- Diabetes
- Proton pump inhibitor use
- Higher clopidogrel loading doses (inverse correlation)
The clinical and genetic models were about equal in their predictive power, but a combined model was significantly better than either alone.
Among the independent factors identified in the study, the researchers noted that the three genes and two of the clinical factors (loading dose and PPI use) were related to clopidogrel. They then called for future studies to determine “whether treatment adjustment on the basis of such global risk stratification can improve the prognosis of patients undergoing PCI.”
October 24th, 2011
New Study Proposes Possible Causative Role for HPV in Atherosclerosis
Larry Husten, PHD
Human papillomavirus (HPV) may play a role in the development of cardiovascular disease (CVD) in women, according to a new study published in the Journal of the American College of Cardiology.
Hus-Ko Kuo and Ken Fujise speculated that HPV may be a risk factor for CVD because it inactivates the tumor-suppressor protein p53, which plays a regulatory role in atherosclerosis. They analyzed data from 2450 women aged 20 to 59, 60 of whom reported having coronary artery disease. About 47% of all the women were HPV-positive, as assessed by a DNA analysis of self-collected vaginal swab specimens.
Among the women with CVD, 39 were HPV-positive while 21 were negative. After adjusting for age and race, the investigators found that HPV elevated the risk for CVD by two-and-a-half times. This increase remained significant when other risk factors were also included in the analysis. Women with cancer-associated HPV types had an even higher risk elevation.
The authors write that to the best of their knowledge there has been “no previous report on the association between HPV and CVD.”
The article is accompanied by an editorial written by Joseph Muhlestein, who more than a decade ago first proposed that a different infectious agent, Chlamydia pneumoniae, might play a causative role in CVD. He writes that
…the present article adds another important infectious candidate to the list of agents associated with the development, progression, or destabilization of atherosclerotic cardiovascular disease. This finding re-emphasizes the potential roles that a variety of chronic infectious agents may play in the pathogenesis of atherosclerosis. Despite setbacks experienced in a number of clinical trials designed to treat patients based on the “infectious hypothesis,” it still lives on, and slowly, progress is being made.
“In the end,” he concludes, “the infectious hypothesis of atherosclerosis may still pan out.”
October 24th, 2011
Midlife Obesity Increases Risk for CHD Mortality
Larry Husten, PHD
Obesity in early adulthood doubles the risk of coronary heart disease (CHD) mortality, but this association is eliminated after midlife BMI is factored into the equation, according to a report in Archives of Internal Medicine.
Linsay Gray and colleagues utilized data from the Harvard Alumni Health Study, which included nearly 19,000 men who were undergraduates between 1916 and 1950 and for whom height and weight data were obtained first at school and then in a follow-up questionnaire. Risk of CHD mortality was nearly doubled in men who were obese as undergraduates (HR 1.83, CI 1.21-2.76), but when midlife BMI was included in a multivariate analysis, the predictive role of early obesity was diminished and lost statistical significance (HR 1.21, CI 0.73- 2.02). Being overweight in middle-age was associated with a significant 25% increase in CHD mortality; being obese in middle age was associated with a significant 60% increase in risk.
In an editor’s note, Archives editor Rita Redberg places the study in the context of the “alarming increase in obesity rates” and writes that the study “brings us some reason for hope.” She concludes that “it is never too late to adopt healthy lifestyle changes.”
October 24th, 2011
Does This Child Have More Than an Arrhythmia?
Thierry Legendre, MD and James Fang, MD
An 11-year-old boy presents with palpitations. He has no family history of heart disease and is asymptomatic while playing competitive sports. His cardiac physical examination is normal, but his ECG (shown below) shows a Wolff-Parkinson-White pattern with a short PR interval and delta waves.
A systematic echocardiogram reveals normal LV function, normal atrioventricular valves, and trabeculations of the LV apex and inferolateral wall. MRI (shown below) confirms the diagnosis of LV noncompaction.
The treating cardiologist decides to explore the possibility of an ablation of the symptomatic preexcitation pathway.
Questions:
- What do you think the patient’s prognosis would be after an ablation?
- Would you prescribe aspirin or other anticoagulation therapy?
- What activity restrictions, if any, would you give the boy after ablation of the accessory pathway?
Response:
November 1, 2011
Cardiac conditions in children are always very agonizing for parents, physicians, and the patient. Getting children to identify their symptoms can also be very difficult.
This 11-year-old boy has WPW and symptoms that, though modest (e.g., palpitations), warrant further investigation. The pathway is probably left-sided and posteroseptal, in that the complexes are negative in the inferior leads and the R wave becomes prominent early over the precordium, increasing the risk for heart block with ablation. However, my non-electrophysiologist’s attempt at localizing the pathway from the 12-lead should be taken with a (large) grain of salt.
In minimally symptomatic or asymptomatic patients, an EP study may be suggested to delineate high-risk features such as inducibility of sustained atrial fibrillation or AV reentrant tachycardia and antegrade conduction of the accessory pathway. In such high-risk situations, multiple pathways are often present, which can make ablation more difficult technically. However, ablative therapy is safe and effective in experienced hands. Getting children to take chronic medications is also challenging, particularly over the long term.
In one of the few randomized experiences I could find, Pappone and colleagues randomized a small group of asymptomatic children with high-risk EP features to ablation or no ablation (N Engl J Med 2004; 351:1197). Ablation appeared to limit the incidence of significant arrhythmias, but the study was small with limited follow-up. Notably, children with evidence of structural heart disease were excluded.
It is unclear to me whether the patient truly has LV noncompaction (LVNC), as most of the criteria for LVNC that I’m aware of are for adults and I don’t know how common abnormal “hypertrabeculation” is on pediatric MRIs. In my experience, LVNC in children is usually associated with other congenital heart defects. Genetic testing can sometimes help to confirm the diagnosis. I am not aware of an association of WPW with LVNC specifically, but there is a well-known association with Epstein’s anomaly. Rarely, WPW can be seen with glycogen storage diseases that may mimic hypertrophic cardiomyopathy (e.g., Danon’s disease), but LVNC is typically related to sarcomeric gene defects. LVNC appears to be inherited in an autosomal dominant pattern, so generations are generally not skipped, which is relevant in this case because no family history is reported.
Here are my answers to the questions:
1. Prognosis should be good following ablation, as the Pappone study illustrates, if there is no concomitant cardiomyopathy (which is, of course, the question at hand).
2. Aspirin or warfarin is not needed, unless by protocol for a few weeks after the procedure (which is likely operator-dependent).
3. I would not restrict the patient’s postprocedure activities on the basis of the MRI findings alone. However, it would be interesting to see what the patient’s postablation EKG looks like, as a clearly abnormal EKG following ablation would favor a diagnosis of a cardiomyopathy.
Update:
November 15, 2011
I referred this patient to a specialized pediatric cardiology unit. The treating clinician has decided to investigate his conduction pathways during the coming months, and he has been prescribed aspirin. Heavy physical activity has been discouraged.
In response to Dr. Fang’s comment, I would like to specify that the association of Wolff-Parkinson-White syndrome and LV noncompaction was described in 4 of 27 pediatric patients by Ichida et al. (J Am Coll Cardiol 1999; 34:233) and in 6 of 36 patients by Pignatelli et al. (Circulation 2003; 108:2672), all without congenital heart defects.
October 20th, 2011
CDC and AHA Tussle Over Just How Bad the Salt Problem Really Is
Larry Husten, PHD
No matter how you slice it, a lot of people in the U.S. consume too much sodium. But the CDC and the American Heart Association (AHA) disagree about just how bad the salt problem really is.
U.S. guidelines currently recommend that everyone keep their daily sodium intake below 2300 mg, but a large subpopulation, including people aged 51 or older, blacks, and people with hypertension, diabetes, or chronic kidney disease, should further restrict their sodium intake below 1500 mg. Now, a report from the CDC finds that nearly half the population (47.6%) should adhere to the more restrictive 1500-mg guideline. The estimate is based on data from the National Health and Nutrition Examination Survey (NHANES).
In a statement issued by the AHA, however, AHA president Gordon Tomaselli says the CDC report is “too conservative in its suggestion that only 47.6 percent of American adults fit into the population group that should be consuming no more than 1500 mg a day of sodium.”
Clyde Yancy, a former AHA president, spells out the reason for the AHA position: “Given that most of us – as many as 90% – will develop high blood pressure with age, we all should be consuming less than 1500 mg a day of sodium, unless your healthcare provider has told you that this doesn’t apply to you.”
No matter the goal, Americans are consuming far too much salt, according to the CDC report. Even with the more conservative CDC guidelines, 98.6% of those with the more restrictive 1500-mg recommendation are exceeding their limit, while 88.2% of the rest of the population is exceeding the 2300-mg limit.
October 20th, 2011
EMA’s CHMP Finds No Cancer Link for ARBs
Larry Husten, PHD
Following the lead of the FDA earlier this year, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has completed a safety review of angiotensin II receptor antagonists (ARBs) and found no evidence of any increased risk of cancer associated with the drugs. The FDA and EMA safety reviews were initially prompted by a meta-analysis in Lancet Oncology by Sipahi and colleagues.
CHMP concluded that “the evidence from the meta-analysis was weak, noting several problems with the quality of the data, specifically that patients in the trials were not followed up for long enough to clearly establish a link between ARBs and cancer, information on the risk of cancer before start of treatment was lacking, and there was a possibility of publication bias, whereby studies that showed a link with cancer were more likely to have been included in the analysis.”
October 19th, 2011
U.K. Registry Tracks Long-Term TAVI Outcomes
Larry Husten, PHD
The excitement over transcatheter aortic valve implantation (TAVI) has been tempered by the absence of long-term outcomes data and concerns that the procedure may not live up to its initial promise in real-world settings. Now a report from the U.K. TAVI Registry, which keeps track of every TAVI procedure performed in the U.K., sheds new light on the long-term outcomes of TAVI in real-world settings.
In a paper published in the Journal of the American College of Cardiology, Neil Moat and colleagues report the results of 877 TAVI procedures performed through 2009 in 870 high-risk patients at 25 centers (with a median of 24 implants per center). Mortality was ascertained in all patients:
- 30-day survival: 92.9%
- 1-year survival: 78.6%
- 2-year survival: 73.7%
Mortality was higher in patients who received a nontransfemoral implant. Independent predictors of mortality were LVEF <30, the presence of moderate or severe aortic regurgitation, and COPD. At 30 days, the rate of stroke was 4.1% and the rate of MI was 1.3%.
The authors conclude that “although 30-day mortality was acceptable, there was a significant attrition between 30 days and 12 months, predominantly in the highest risk cohort.” The results support a randomized trial comparing TAVI to surgery in a less high-risk group of patients, they say.
In an accompanying editorial, Alec Vahanian, Dominique Himbert, and Bernard Iung write that the registry supports the use of TAVI in “high-risk or inoperable patients, when performed in properly trained centers.” Future efforts, they add, “should aim at improving patient selection both by a dedicated medicosurgical team and by improving procedural performance through careful training and improvement in technology.”
October 19th, 2011
First-Trimester Hypertension, Not ACE Inhibitors, Linked to Birth Defects
Larry Husten, PHD
Although the teratogenic properties of ACE inhibitors in the second and third trimesters of pregnancy are well-documented, the effects of their use in the first trimester have been unclear. Now a study suggests that hypertension itself, rather than ACE inhibitors or other antihypertensive drugs, is the likely cause of an increased risk for birth defects in this population.
In a paper published in BMJ, De-Kun Li and colleagues analyzed Kaiser Permanente data from 465,754 mother-infant pairs in Northern California from 1995 to 2008. After adjustment for other risk factors, mothers who used ACE inhibitors in the first trimester had an increased risk for congenital heart defects in their offspring only when compared with “normal” controls (i.e, mothers without hypertension). No significant elevation in risk was observed when ACE inhibitor users were compared either with women who used other antihypertensives or with hypertensive controls (i.e, women with untreated hypertension).
The authors concluded:
Maternal use of ACE inhibitors in the first trimester has a risk profile similar to the use of other antihypertensives regarding malformations in live born offspring. The apparent increased risk of malformations associated with use of ACE inhibitors (and other antihypertensives) in the first trimester is likely due to the underlying hypertension rather than the medications.
In an accompanying editorial, Allen Mitchell writes that on the basis of this and previous studies “it is reasonable to conclude that exposure to ACE inhibitors during the first trimester poses no greater risk of birth defects than exposure to other antihypertensives.” He also discusses the implications of the finding that hypertension can cause birth defects, and wonders if there are “physiological changes that might affect fetal development before they manifest as increased maternal blood pressure.”
October 18th, 2011
Heart Failure Hospitalization Rate Drops 30% in 10 Years
Larry Husten, PHD
From 1998 through 2008, the rate of heart failure hospitalization in an elderly Medicare population declined by nearly 30%, according to a new study published in JAMA.
Jersey Chen and colleagues (including senior author Harlan Krumholz, editor-in-chief of CardioExchange) analyzed CMS data from 55 million fee-for-service Medicare patients hospitalized for heart failure between 1998 and 2008. After adjusting for age, sex, and race, the investigators found that the hospitalization rate dropped over the period from 2845 to 2oo7 per 100,000 person-years (P<0.001), a relative decline of 29.5%. Although a decline was observed in all race-sex categories, the slowest rate of decline was observed in black men (from 4142 to 3201 per 100,000 person-years).
The authors calculated that the decline in the hospitalization rate resulted in 229,000 fewer hospitalizations in 2008, yielding a savings of $4.1 billion in fee-for-service Medicare. A statistically significant but modest 6.6% relative decline in 1-year mortality was also observed, from 31.7% in 1999 to 29.6% in 2008 (P<0.001).
In an accompanying editorial, Mihai Gheorghiade and Eugene Braunwald write that although the study demonstrates some progress, “the overall mortality rate and readmission rate for HF continue to remain unacceptably high.” They suggest several strategies to improve outcomes in HF patients, including a more aggressive strategy to treat subclinical congestion, treatment of cardiac abnormalities and noncardiac cormorbidities, better postdischarge follow-up, and greater utilization of underused agents like digoxin and eplerenone.
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