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SHIFT investigators reported at the 2011 European Society of Cardiology Congress in Paris, France, and published in the European Heart Journal, the heart-rate lowering drug ivabradine has been shown to reverse left ventricular (LV) remodeling in patients with heart failure (HF). The investigators believe that this effect of ivabradine “may contribute to the reduction in cardiac morbidity and mortality found in patients with HF.”

Ivabradine specifically inhibits the If current in the sinoatrial node and, in patients with HF, has been associated with a reduction in risk of cardiovascular death or hospitalization—the primary end point of SHIFT. In this prespecified substudy, echocardiographic analysis from 411 patients was used to evaluate the effects of ivabradine on LV remodeling and function.

Compared with placebo, ivabradine (mean dose 6.0 ± 1.6 mg twice daily) was associated with a reduction (?5.8 ± 1.6 ml/m2, 95% CI ?8.8 to ?2.7, P <0.001) in LV end-systolic volume index after 8 months of treatment—the primary end point of the substudy. Reductions in LV end-diastolic volume index (?5.5 ± 1.8 ml/m2, 95% CI ?8.9 to ?2.0, P = 0.002), LV end-systolic volume (?11.2 ± 3.0 ml, 95% CI ?17.1 to ?5.4, P <0.001), and LV end-diastolic volume (?10.9 ± 3.4 ml, 95% CI ?17.6 to ?4.2, P = 0.001) were also associated with ivabradine therapy over the same period, as was an increase in LV ejection fraction (2.7 ± 0.8%, 95% CI 1.3–4.2, P <0.001).

The SHIFT investigators highlight that their substudy results are in line with those of the BEAUTIFUL trial of ivabradine in patients with stable coronary artery disease and LV systolic dysfunction.

Reference

Tardif, J.-C. et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur. Heart J. doi: 10.1093/eurheart/ehr311

By:  Oscar Millan-Iturbe, MD / MPH

@ozkr_millan

The first report from the United Kingdom Transcatheter Aortic Valve Implantation (UK TAVI) Registry provides important new information on the mid-term and long-term outcomes of patients with severe, symptomatic aortic stenosis (AS) undergoing this procedure. Moat and colleagues write that this study is “unique in that it has captured every TAVI performed … within England and Wales, and thus includes the entire ‘learning curve’ and early experience of adopting centers without any publication bias.”

The earlier Placement of Aortic Transcatheter Valve (PARTNER) trial provided seminal data on 30-day and 1-year outcomes of patients with AS who were candidates for surgery (cohort A) or in whom the surgical risk was considered too great (cohort B). However, the enrollment criteria of the PARTNER trial were highly defined and, therefore, the characteristics of these patients are not necessarily representative of individuals undergoing TAVI in the real world. The findings from the UK TAVI Registry are thus a welcome addition to the literature.

In their paper, Moat et al. report data spanning the period from the first implantation conducted in the UK in January 2007, up to the end of December 2009. All 25 TAVI centers in England and Wales provided information on every procedure performed—a total of 870 patients (877 implants). The mean age of patients was 81.9 years.

The number of TAVIs increased from 66 in 2007 to 538 in 2009. Patient mortality was calculated up to 12 December 2010 (range of follow-up: 11–46 months). Two valve prostheses were available for implantation—the Edwards SAPIEN^® (Edwards Lifesciences, Irvine, CA, USA) and the CoreValve^® (Medtronic CV Luxembourg S.a.r.l, Luxembourg), which were used in 410 and 452 patients, respectively. The majority (69%) of patients underwent transfemoral TAVI (90% of CoreValve^® prostheses were implanted this way); however, approximately half of the Edwards SAPIEN^®valves were implanted transapically. Patients whose procedures were conducted with a nontransfemoral approach had a higher prevalence of coronary artery and peripheral vascular diseases, renal dysfunction, and more-severe symptoms than those who underwent a transfemoral procedure.

No differences in the incidence of myocardial infarction or stroke at 30 days were evident between transfemoral and nontransfemoral access or between the two devices. However, a pacemaker was needed more often in those with a CoreValve^® than in those with a SAPIEN^®. The CoreValve^® was also associated with a increased incidence of paravalvular aortic regurgitation (AR). Survival at 30 days, 1 year, and 2 years among the whole cohort was 92.9%, 78.6%, and 73.7%, respectively. The rate of death declined with time; 21.4% of patients died within the first year, but only 4.9% died between 1 and 2 years. Nontransfemoral access was associated with greater mortality than transfemoral access at all time points. No mortality difference was observed between the two types of valve. In multivariate analysis, the only independent predictors of mortality were chronic obstructive pulmonary disease, left ventricular ejection fraction <30%, and moderate or severe AR. This last factor is noteworthy, as 61% of patients in the registry had some degree of AR. Continued analysis of data from this ongoing registry will increase our knowledge of TAVI and guide procedures well into the future.

Oscar Millan-Iturbe, MD MPH

Twitter:    @ozkr_millan

 References

1. Moat, N. E. et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the UK TAVI (United Kingdon Transcatheter Aortic Valve Implantation) Registry. J. Am. Coll. Cardiol. doi: 10.1016/j.jacc.2011.08.050

By Oscar Millan Iturbe  MD/MPH         @ozkr_millan

I would like to comment the new study led by Dr Shunichi Homma and Dr John (Seamus) Thompson, the use of warfarin or aspirin have been compared for thromboprophylaxsis in patients with heart failure (HF) and sinus rhythm. On the basis of their findings, the investigators conclude that “there is no compelling reason to use warfarin rather than aspirin in patients with a reduced left ventricular ejection fraction who are in sinus rhythm.”

In total, 2,305 patients from 168 centers in 11 countries were enrolled in the double-blind, double-dummy, randomized WARCEF trial. The mean left ventricular ejection fraction for the enrolled patients was 24.7%. Mean follow-up time was 3.5 years. Total follow-up time was 8,225 patient-years. Patients in the warfarin group had an INR in the therapeutic range (2.0–3.5) for 63% of the total treatment time.

The primary outcome—first incidence of ischemic stroke, intracerebral hemorrhage, or death—occurred at rates of 7.47 and 7.93 events per 100 patient-years in the warfarin and aspirin groups, respectively (HR for warfarin 0.93, 95% CI 0.79–1.10, P = 0.40). Although no significant difference was observed overall, time-varying analysis did demonstrate a small benefit of warfarin over aspirin with time, which was statistically significant by year 4 (HR for warfarin 0.76, P = 0.04). However, the investigators point out that this benefit “was of borderline statistical significance and uncertain clinical significance”.

The rates of death, intracerebral hemorrhage, myocardial infarction, and hospitalization for HF did not differ significantly between the two treatment groups. Warfarin was associated with approximately half as many ischemic strokes, but twice as many major hemorrhages and gastrointestinal bleeds, and ~50% higher rates of minor hemorrhage compared with aspirin.

“We will look for a subgroup that may benefit from warfarin or aspirin, so that one can tailor the therapy,” says Dr Homma. The WARCEF investigators also point out in their report that newer antithrombotic agents might prove to be more effective than either of the agents compared in this trial. Indeed, Dr Homma tells us that they are planning to test the newer antithrombotic agents in these patients.

Reference

1. Homma, S. et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N. Engl. J. Med. doi: 10.1056/NEJMoa1202299

Despite multiple studies comparing the effects of rosuvastatin and atorvastatin on blood lipid levels, no previous randomized, controlled trial has compared the direct effects of these statins on atherosclerotic progression. Nicholls and colleagues therefore used intravascular ultrasonography to compare the effects of maximal doses of rosuvastatin (40 mg daily) or atorvastatin (80 mg daily) on atherosclerotic plaque size in the coronary arteries of 1,039 patients.

Rosuvastatin and atorvastatin were both associated with small but significant reductions in percent atheroma volume, the primary efficacy end point, over the 104-week follow-up period (median changes of ?1.22% for rosuvastatin, and ?0.99% for atorvastatin, P<0.001 for both; P = 0.17 for between-group comparison). Reduction in percent atheroma volume was noted in 68.5% and 63.2% of the rosuvastatin and atorvastatin groups, respectively (P = 0.07). For total atheroma volume—the secondary efficacy end point—modestly greater reductions were found in the rosuvastatin group compared with the atorvastatin group (?6.39 mm³ vs ?4.42 mm³, P = 0.01), and more patients in the rosuvastatin group exhibited disease regression (71.3% vs 64.7%, P = 0.02).

At the 104-week follow-up, levels of LDL cholesterol were 7.5 mg/dl lower in the rosuvastatin group than in the atorvastatin group (62.6 ± 1.0 mg/dl vs 70.2 ± 1.0 mg/dl,P <0.001). Accordingly, more patients in the rosuvastatin group had LDL-cholesterol levels below current treatment targets of 100 mg/dl (95.4% vs 92.3%, P = 0.04), and 70 mg/dl (72.1% vs 56.1%, P <0.001). Rosuvastatin was also associated with 1.8 mg/dl higher HDL-cholesterol levels than atorvastatin (50.4 ± 0.5 mg/dl vs 48.6 ± 0.5 mg/dl, P= 0.01).

The researchers point out that their data “indicate that coronary artery disease can regress if the favorable levels of LDL and HDL cholesterol … attained with statin therapy in this study are achieved,” and recommend “further study in clinical trials.”

ORIGINAL RESEARCH PAPER

1. Nicholls, S. J. et al. Effect of two intensive statin regimens on progression of coronary disease. N. Engl. J. Med. doi: 10.1056/NEJMoa1110874

By Oscar Millan-Iturbe MD, MPH                                                     @ozkr_millan

I would like to present this meta-analysis of randomised controlled trials published in the British Journal “Heart”. The meta-analysis compares outcomes of transradial versus the transfemoral route. P atients with ST-segment elevation myocardial infarction (STEMI) who undergo percutaneous coronary intervention (PCI) are at high risk of bleeding complications and, therefore, of other adverse events, such as death, reinfarction, and stroke. Authors of a new meta-analysis assessing the impact of access site on patient outcomes have shown reduced adverse events when radial access is used for STEMI PCI.

Although a previous meta-analysis suggested that radial access is associated with various benefits, Mamas et al. felt that “many of the enrolled studies had a suboptimal (and often nonrandomized) design.” Because of this, and because “recent publication of the RIVAL study has provided substantial new data,” they performed a new meta-analysis “to better define best practice in this high-risk group”.

Data from nine published, randomized, controlled studies that compared the outcomes for 2,977 patients with STEMI who had undergone PCI via a radial or femoral access site were incorporated into the analysis. RIVAL was the largest of the included trials, with 1,958 individuals (that is, 66% of all included patients); the other eight studies each involved between 50 and 200 patients.

Access-site complications were 70% less likely in the radial-access group than in the femoral-access group (OR 0.30; 95% CI 0.19–0.48; P <0.0001). In line with this finding, major bleeding events (1.2% vs 2.3%; OR 0.55; 95% CI 0.31–0.99; P = 0.049), major adverse cardiac events (3.2% vs 5.1%; OR 0.62; 95% CI 0.43–0.90; P = 0.012), and mortality (1.9% vs 3.6%; OR 0.52; 95% CI 0.33–0.83; P = 0.006) were all significantly lower with transradial PCI. No heterogeneity was found between the included studies.

The authors point out that “adoption of the transradial route would only be expected to reduce bleeding complications from the access site,” and highlight that, “risk of major bleeding, even if performed through the transradial route, … still remained significant.”

Mamas et al. thus conclude that “PCI patients will benefit from the adoption of safest access-site practice (use of the transradial approach) in combination with an antithrombotic regimen optimized to preserve anti-ischemic efficacy but minimize systemic bleeding.” They caution, however, that an urgent need exists for a single adequately powered, randomized, controlled study, and that (in the meantime) “the radial approach is associated with an important learning curve. Before embarking on a transradial STEMI program, operators and institutions must develop their skills in less-challenging patient populations.”

Reference

Mamas, M. A. et al. Influence of access site selection on PCI-related adverse events in patients with STEMI: meta-analysis of randomised controlled trials. Heart doi: 10.1136/heartjnl-2011-300558

By Oscar Millan-Iturbe
@ozkr_millan

It is important to identify the association between high uric acid levels and its link with acute coronary syndromes. In the past Annual Scientific Session & Expo taken place in Chicago, there was a session devoted to this issue. I found this article which depicts a little bit the association. “Elevated levels of uric acid predict an increased risk of 1-year mortality across the whole spectrum of patients with acute coronary syndrome (ACS),” suggests Gjin Ndrepepa, the lead investigator in a study published in the American Journal of Cardiology.

The team from the German Heart Centre in Munich retrospectively analyzed prospectively collected data from 5,124 patients with confirmed ACS who underwent percutaneous coronary intervention (PCI). They grouped the patients in quartiles according to their plasma uric acid concentration (quartile 1, 1.3 mg/dl to <5.3 mg/dl; quartile 2, 5.3 mg/dl to <6.3 mg/dl; quartile 3, 6.3 mg/dl to <7.5 mg/dl; and quartile 4, 7.5 mg/dl to 18.4 mg/dl). The primary end point was 1-year all-cause mortality and the association between uric acid levels and risk for mortality was assessed according to the patients’ clinical presentation (STEMI, NSTEMI, and unstable angina).
Within the first year after PCI, a total of 450 deaths were reported. The number of deaths was higher among patients in quartile 4 than among those in quartiles 1–3 in all subgroups. After adjustment for traditional cardiovascular risk factors, 1-year mortality was found to be increased by 12% for every 1 mg/dl increase in uric acid concentration.

“We are interested in now assessing the impact of uric acid on the extension and severity of coronary atherosclerosis,” Ndrepepa says. Although uric acid levels seem to provide prognostic information incremental to that provided by conventional risk factors—at least in terms of mortality—the mechanisms involved in the detrimental effects of high uric acid levels are not yet known.

Reference:
Ndrepepa, G. et al. Prognostic value of uric acid in patients with acute coronary syndromes. Am. J. Cardiol. doi: 10.1016/j.amjcard.2011.12.018

The medical clinical case this week is a 55 year old comes in for episodes of regular and rapid heartbeats, upset at the neck associated with mild dyspnea, diaphoresis and cool skin. These episodes have duration of 20 to 40 minutes, with a frequency of 1 to 2 weeks. He has a history of significant hypertension for 14 years of diagnosis. Physical examination revealed hemodynamic stability, heart rate of 77 bpm, oxygen sat 98%. Cardiovascular examination with rhythmic heart sounds, no S3 or S4, no murmurs. Rest without relevant findings.

During the medical consultation, the family keeps an ECG that was taken in an episode of palpitations in a clinic closer to home. The line is of poor quality and is poorly preserved, but its diagnostic value includes it here:

Any comment you may have please twitt us @cardiodata_en

By Oscar Millan-Iturbe  MD/MPH

@ozkr_millan

By Oscar Millan-Iturbe MD / MPH

@ozkr_millan

I found this fascinating article; hopefully all of you can review it in full text. Basically it is an investigation from European and Australian researchers whom give an explanation for why men have an increased risk of coronary artery disease compared with women. In their report published in the Lancet, the investigators conclude that a particular Y chromosome haplotype is associated with increased risk of CAD in men of European origin. They note that this association “might be mediated through a genetically programmed profile of immunity and response to inflammation.”

Dr. Fadi Charchar and colleagues performed a cross-sectional case–control analysis of 633 white, British men with no known history of CAD (controls) and 811 white, British men with a validated history of CAD and a strong family history of the condition. One Y chromosome haplotype, called ‘I’, was associated with a 75% increase in risk of CAD (age-adjusted OR 1.75, 95% CI 1.20–2.54, P = 0.004).

The association of haplotype I with the prospective development of CAD was confirmed (age-adjusted OR 1.45, 95% CI 1.08–1.95, P = 0.012) in a group of 1,534 Scottish men who had been involved in a clinical trial assessing statin-mediated primary prevention of CAD. No cardiovascular risk factors (including alcohol consumption, blood pressure, BMI, C-reactive protein level, diabetes mellitus, glucose level, lipid levels, or smoking status) or socioeconomic factors (such as education level and employment status) were associated with the haplotype. After combining the data from the two analyses, the researchers concluded that Y chromosome haplotype I increased risk of CAD by approximately 50%.

In subsequent analysis of the monocyte and macrophage transcriptomes, Charchar et al. found that 19 molecular pathways related to inflammation and immunity in the macrophage were altered in men with haplotype I compared with carriers of other haplotypes. By contrast, no changes in monocyte pathways were associated with haplotype I. The investigators speculate that this finding “suggests that differentiation (activation) of monocytes to macrophages, one of the key steps in the pathogenesis of atherosclerosis, might be the stage at which haplotype I exerts its molecular effects on CAD.”

Reference

Charchar, F. J. et al. Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome. Lancet doi: 10.1016/S0140-6736(11)61453-0

It is possible that 1 out of 3 teenagers will start in the consumption of tobacco influenced by direct or indirect ads, through the sponsorship of sporting activities, parties, gifts, or by certain media leaders (actors, musicians, artists …) who are shown smoking in movies, concerts or interviews (Pierce, 1998, p511).

Tobacco advertising has been misleading and recently the industry has publicly acknowledged that the tobacco cause harm, and that consumption of cigarettes is highly addictive (but without actually admitting it is a drug). Tobacco publicity is perverted and at the same time technically perfect. Tobacco companies intend to sell the idea that consumption of cigarettes is an exercise of freedom and independence and a symbol of transition to adulthood. They try to associate the image of the cigarette to the social success or winners. The present paper analyzes the ethical issues in relation to the ban on all forms of tobacco advertising and sponsorship. Furthermore, this essay will argue the importance on the total ban on advertising practices of tobacco. Finally, I will propose a strategic advocacy plan which may support the total ban on tobacco advertising and sponsorship.

Tobacco is a product that not only is still producing and selling, but it is announced in bulk in any media or advertising space. In fact, in our present society snuff and advertising are closely tied, this close relationship means that there are some ethical situations that may be caused by the acceptance or banning ads from the tobacco industry.

Supporters of tobacco advertising argue that the tobacco must have the same rights of equivalence in relation to other retail product and services, and note that the restrictions or bans in promoting their products incurs on unjust and discriminatory actions (Chapman, 1996, p122 ). Most often the information presented in tobacco advertisings is misleading and this undoubtedly represents an unethical action because there is no mention of the price and a detailed description of the harms that the may cause.

The exercise of selectivity in constructing advertisings is misleading to consumers because it does not fully describe every possible facet of the product and consequence of it use. Tobacco advertisings are lying when they try to promote their products because most of the time the advertisements contain positive associations about tobacco, smoking and smokers (Chapman 1996, p 124). It is well known the impacts on health that can arise from the consumption of tobacco, but tobacco companies continue or insist on presenting a positive image when promoting their products.

Tobacco industry construct advertisements designed to mock, distract and generally undermine such health warnings (Chapman 1996, p 125). This action is certainly seen as an unethical act and the omission of information would result in consumers being mislead.

“Defenders of tobacco advertising tend to assume a free market philosophy where restrictions on advertising are seen as ethically offensive to the sovereignty of business interests” (Chapman, 1996, p127). However, governments have the right to implement restrictions and bans on advertising as they must protect consumers from unsafe goods and thus avoid promoting unhealthy products to the community.

Despite the arguments of the tobacco industry, various researchers have found that advertising is an important factor in the consumption of tobacco among children and adolescents (Gilpin et al, 1997, p 1229). For example, Biener et al, have shown that the probability of adolescent who do not smoke and that received a promotional item provided by tobacco companies, become smokers twice compared with those who had not received it (Biener et al, 2000, p407). Indeed, such is the power that advertising can accumulate that it is essential the restrictions or bans from a legislative point of view, to prevent possible misuses of it.

Prompted by the alarming rates in morbidity and mortality associated with smoking, its social health cost and the emergence of the first evidence that linked the effects of tobacco advertisings on the role of consumption, several countries began to put restrictions on such advertisings. Ruth Roemer’s 1993 Current cited by Chapman (1996, p121) mention that 27 countries in the world have a complete ban on tobacco advertising, with a further 77 having some form of restriction.

Tobacco companies have always avoided any reference to the problems that tobacco creates. The sponsorship of events of interest (preferably sporting), the financing of films and television programs with the condition that their players smoke (looking for the effect that this model can cause), are some examples of strategies implemented by the tobacco industry which main goal is to promote their products. By this actions, tobacco advertising is dressed of innocence aiming to avoid, at least on paper, some of the bans imposed to their products.

The relationship between sport and tobacco began more than a century ago, when in cigarette packs of England and America appeared the myths of the moment in cricket or baseball (Holman et al, 1997, p115). Since then many athletes have lent their image for this advertisements and have sponsored many sporting activities by large companies. This interest was focused in those sports that have become more attractive (and therefore a wider audience) for the general population. Among them, racing motorcycles and cars have always occupied a central target for the tobacco industry. With these investments, tobacco companies pursue several goals: to reach potential consumers, associate tobacco for promotional purposes to the innate values of sport, wash their image challenged by society, and get profits.

Marlboro, a Philip Morris brand, has been a long-time sponsor of Formula One (F1) and Indy Car racing as part of a deliberate project to complement and extend the brand’s established “lone cowboy” image with contemporary sports (Dewhirst et al, 2003, p372). “A single grand prix provides the equivalent of about fifty 30­second cigarette advertisements, and children’s recall of brand imagery is high” (Chambers, 1999, p1). This is why tobacco companies are seeking to sponsor sporting events of great magnitude in order to promote their products and incur in unethical behaviors.

It is clear that by its very nature, advertising tends to seek the maximum expansion of the sales of a product, in order to maintain the productive machinery that sustains the product. In this context, the tobacco industry is trying to defend the maintenance of its advertising through the following arguments:
• If tobacco is a legal product, their promotion should remain legal.
• Advertising on tobacco is not designed to influence the overall demand of the product, but to redistribute the market between the different brands.
• Advertising is directed only to the adult population as a consumer, not to childhood or adolescents.
• Advertising provides consumers with relevant information about the brands offered in the market and, therefore it is an effective tool of information to consumers.

Finally, there is evidence in the literature that supports the restriction or prohibition on tobacco advertising produced by the industry. I think it is necessary to continue these actions, countries that still do not take these actions must consider the implementation of actions that restrict the promotion of tobacco. It is important to ban any direct or indirect promotion of tobacco products in all media including the Internet. Sporting events sponsored by the tobacco industry should not display advertisements during these events, because the sport is a common good for society and the promotion of cigarette poses a health risk for the community.

By Oscar Millan-Iturbe, M.D./M.P.H.
@ozkr_millan
@cardiodata_en

References:

Biener L, Siegel M. Tobacco marketing and adolescent smoking: more support for a causal inference. American Journal of Public Health 2000; 90: 407-11.

Chambers, Jacky. Being strategic about smoking. British Medical Journal 1999;318:1–2

Chapman, Simon. The ethics of tobacco advertising and advertising bans. British Medical Bulletin 1996, 52:121-131

Dewhirst, Timothy; Sparks. Intertextuality, Tobacco Sponsorship of Sports, and Adolescent Male Smoking Culture: A Selective Review of Tobacco Industry Documents, Journal Of Sport & Social Issues, vol. 27, no. 4, pp. 372-398, November 2003.

Gilpin E, Pierce J. Trends in adolescent smoking initiation in the United States: is tobacco marketing an influence? Tobacco Control 1997; 6: 122-7

Holman CDJ, Donovan RJ, Corti B, Jalleh G, Fritzzell SK, Carroll AM. Banning tobacco sponsorship: replacing tobacco with health messages and creating health-promoting environments. Tobacco Control 1997; 6: 115-21.

Pierce JO, Choi WS, Gilpin EA, Farkas AJ, Berry CC. Tobacco industry promotion of cigarettes and adolescent smoking. JAMA 1998;279:511-5