The addition of aliskiren, a novel direct renin inhibitor that lowers plasma renin activity, to standard therapy (an angiotensin-converting enzyme [ACE] inhibitor or an angiotensin receptor blocker [ARB]) did not improve outcomes for people with type 2 diabetes and renal impairment who are at high risk for cardiovascular (CV) and renal events. This finding is among the preliminary results of Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints [ALTITUDE; NCT00549757], which was stopped early in December 2011 because of futility and a high rate of adverse events in the aliskiren group. Using aliskiren with an ACE inhibitor or ARB in this population is not recommended and may even be harmful, said Hans-Henrik Parving, MD, DMSc, University of Copenhagen, Copenhagen, and Aarhus University, Aarhus, Denmark, who presented the findings.
ALTITUDE included 8561 patients who were randomly assigned to treatment with standard therapy (an ACE inhibitor or ARB) plus aliskiren, 150 mg QD for 1 month, followed by 300 mg QD (4272 patients) or placebo (4285 patients). All patients had type 2 diabetes, renal dysfunction, and were at high risk for CV disease. The trial was designed to determine if the addition of aliskiren would provide better cardiorenal protection than monotherapy.
The primary endpoint was a composite of CV and renal outcomes, including CV death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or renal death, or doubling of the baseline serum creatinine level (sustained for at least 1 month).
At a median follow-up of 32 months, the rate of the composite endpoint was 17.9% in the aliskiren group and 16.8% in the placebo group (HR, 1.08; 95% CI, 0.98 to 1.20; p=0.14). Prof. Parving noted that when the individual components of the endpoint were analyzed separately, some occurred more frequently in the aliskiren group, but the differences were not significant (Table 1).
Table 1. ALTITUDE HRs for Individual Components of the Primary Endpoint.
CV=cardiovascular; MI=myocardial infarction; RD=renal disease.
Hyperkalemia was the most common adverse event in the aliskiren group (38.7% vs 28.6%). Among the patients in that group, 8.8% had a serum potassium level ≥6 mmol/L, compared with 5.6% in the placebo group. The serum potassium level was ≥5.5 to 6.0 mmol/L in 21.0% of the aliskiren group and 16.0% of the placebo group. One death was associated with hyperkalemia. Other frequent adverse events in the aliskiren group included hypotension (12.1% vs 8.0%), diarrhea (9.6% vs 7.2%), and falls (2.8% vs 2.6%).
In discussing the study, Johannes Mann, MD, Friedrich Alexander University, Erlangen, Germany, and McMaster University, Hamilton, Ontario, Canada, noted that the reason for a possible increased risk of stroke was unclear. Dual inhibition of the renin system was not associated with such an increased risk in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial [ONTARGET], in which the combination of ramipril (an ACE inhibitor) and telmisartan (an ARB) was compared with each drug used as monotherapy [Tobe SW et al. Circulation 2011]. Both Prof. Mann and Prof. Parving said that the observed risk could be a direct effect of aliskiren or could be a chance finding.
Results from the Prospective Urban Rural Epidemiology [PURE] study, presented by Salim Yusuf, MD, McMaster University, Hamilton, Ontario, Canada, indicated that different strategies are needed to influence health behaviors in countries, depending upon their socioeconomic status. In relatively low-income countries, key strategies include making healthy foods accessible and affordable, and promoting smoking cessation. Among relatively more high-income/industrialized countries, efforts should be focused on increasing physical activity and decreasing fat consumption, while continuing to promote smoking cessation.
Diet, physical activity, and smoking account for 50% to 60% of the risk for cardiovascular disease (CVD) [Yusuf S et al. Lancet 2004; Tu JV. Lancet 2010]; however, these factors vary markedly both across and within countries, due to environmental and societal factors. The PURE study was designed to create an understanding of these factors in order to develop contextually appropriate strategies for CVD prevention.
The PURE study was comprised of 153,996 individuals (aged 35 to 70 years; 42.1% men) from 348 urban and 280 rural communities in 17 low-, middle-, and high-income countries for whom data on diet, physical activity, and smoking were collected during 2003-2010. Validated food frequency questionnaires were used to record diet; physical activity (recreational and nonrecreational/obligatory) was collected using the International Physical Activity Questionnaire. These factors, plus smoking prevalence (ever, current, and quitting) were then related to country gross domestic product (GDP; World Bank statistics) and household wealth (wealth index) overall and separately for individuals from urban and rural areas.
Results from the PURE study showed that among those living in low-income countries there is less consumption of fruits, vegetables, proteins and fats, and a higher consumption of carbohydrates, which researchers attributed to the affordability of different foods. Activity levels were higher in low-income countries due to a higher level of obligatory physical activities (mostly work and transportation-related). Smoking was also more prevalent among individuals in low-income countries. As country GDP increased, there was an increased consumption of fruits and vegetables, accompanied by a higher percentage of energy obtained from total (but not saturated) fats and proteins, with a lower percentage of energy from carbohydrates. Physical activity declined with increasing GDP mostly because of a marked decline in obligatory/nonrecreational activity that was not compensated for by an increase in recreational physical activity. In all categories studied, the association of household wealth to diet, physical activity, and quitting smoking were similar to that observed for GDP.
"Policies to prevent CVD need to focus on different aspects of lifestyle among the rich versus the poor and between rich and poor countries,” said Prof. Yusuf. "In particular, healthy foods need to become more affordable.”
Despite substantial differences in the risk profiles of men and women with stable coronary artery disease (CAD), outcomes at 1 year appear to be similar, according to an analysis of data from the international Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease [CLARIFY; Steg PG et al. Eur Heart J 2012] registry. The study adds new insights into gender differences in stable CAD, as relatively few studies have compared outcomes in this patient population. However, results should be interpreted in the context of an observational registry data set.
The study included data for 30,977 outpatients with stable CAD, defined as prior myocardial infarction (MI), angiographic coronary disease (>50% lesion), ischemic symptoms and a positive stress test, or prior coronary revascularization from 45 countries; 23,975 (77.4%) of the patients were men. The main outcome was a composite of cardiovascular (CV) death, MI, or stroke. Analyses were time to first event, and comparisons by gender were adjusted for differences in patient baseline characteristics.
At 1 year, the rate of the primary outcome was similar for men and women (adjusted rates, 1.7% vs 1.8%, respectively; OR, 0.93; 95% CI, 0.75 to 1.15; p=0.5), reported Philippe Gabriel Steg, MD, Hôpital Bichat, Paris, France, who presented the findings of the study. Women were at similar risk as men for major CV outcomes (Figure 1). Prof. Steg added that there was an interaction between gender and age, with younger women having slightly better outcomes than younger men; however, the same was not true for middle-aged or older women (p-interaction=0.0077).
The risk profile differed substantially by gender, with women more likely to have hypertension or diabetes (Table 1). Women were also more likely to have angina but were less likely to have had diagnostic non-invasive testing or coronary angiography, to have received evidence-based pharmacologic treatments, or to have had revascularization (Table 1).
Figure 1. Major CV Outcomes at 1 Year.
CABG=coronary artery bypass grafting; CV=cardiovascular; MI=myocardial infarction; PCI=percutaneous coronary intervention. Reproduced with permission from the European Society of Cardiology. All rights reserved. Copyright © 2012.
Table 1. Gender Differences in Stable CAD in CLARIFY.
ACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker; CABG=coronary artery bypass grafting; CAD=coronary artery disease; MI=myocardial infarction; PCI=percutaneous coronary intervention; TIA=transient ischemic attack.
Prof. Steg noted several limitations to the study. The primary limitation was the relatively low number of women, which he noted may have been related to the inclusion criteria required by the study. In addition, the cohort sample may not be representative of a population-based sample, as physician and patient participation in the CLARIFY registry is voluntary. Also, despite adjustments for potential confounders, residual confounding cannot be excluded.
Approximately two thirds of patients can tolerate extended-release (ER) niacin when combined with laropiprant, according to a prespecified interim safety and tolerability analysis of the Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events [HPS2-THRIVE; NCT00461630] study. The addition of niacin/laropiprant to statin therapy offers a dual goal of decreasing low-density lipoprotein-cholesterol (LDL-C) and increasing high-density lipoprotein-cholesterol (HDL-C).
Niacin, the first lipid-modifying drug, is one of the most effective agents for increasing HDL-C levels. However, its use has been limited by its side effects, particularly flushing. Coadministration of laropiprant, a selective prostaglandin D antagonist, has been shown to reduce flushing. However, the drug may not reduce this side effect in all patients, as flushing can occur through other pathways.
HPS2-THRIVE includes more than 25,000 patients in Europe and China who have cardiovascular disease (CVD) and are at high risk for recurrent vascular events. The patients were randomly assigned to ER niacin 2 g/laropiprant or to placebo. All patients also received LDL-C reducing therapy with simvastatin 40 mg, with or without ezetimibe 10 mg. The study is the largest one to date to evaluate the CV benefits of increasing HDL-C levels. Jane Armitage, MD, Oxford Clinical Trial Service, Oxford, United Kingdom, reported on the safety and tolerability of the combination drug.
Patients were treated with ER niacin/laropiprant or placebo during an 8-week run-in phase prior to randomization. During this phase, 25.4% of patients in the ER niacin/laropiprant group withdrew from therapy for any medical reason; the primary reasons were cutaneous effects (primarily flushing, 11.3%) and gastrointestinal symptoms (5.5%). An additional 8.7% of patients in this group withdrew during the randomized treatment phase, again primarily because of cutaneous effects (5.1%) and gastrointestinal symptoms (3.6%). Among patients in the placebo group, 1.2% withdrew during the treatment phase because of cutaneous effects and 1.6% because of gastrointestinal symptoms.
Prof. Armitage noted that ER niacin/laropiprant was associated with a high rate of myopathy (1.13% vs 0.18% in the placebo group). This finding was seen primarily in patients of Chinese descent (62 of 69 patients with myopathy were from China). Overall, rhabdomyolysis was rare (0.05% in the treatment group and 0.02% in the placebo group). The identification of an increased risk of myopathy with niacin and simvastatin prompted the following change to the simvastatin label: "Patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products.”
Prof. Armitage reported that during the run-in phase, LDL-C levels were reduced by 20% and HDL-C levels were increased by 17%. These results differ from those in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes [AIM-HIGH] trial, in which LDL-C levels were reduced 5.5% and HDL-C levels were increased by 13.2% [AIM-HIGH Investigators. N Engl J Med 2011]. The AIM-HIGH trial was stopped early because of a lack of benefit of niacin. Whether the more favorable effects on LDL-C lowering and HDL-C raising in HPS2-THRIVE and better tolerability of niacin when combined with laropiprant will translate into a reduction in vascular events will have to wait until the presentation of the study's primary efficacy results in 2013.
A landmark analysis is providing insight into the relationship between resting heart rate and outcomes after ischemic stroke. An analysis of data from the 20,165 patients enrolled in the Prevention Regimen for Effectively Avoiding Second Stroke [PRoFESS] study showed that heart rate is associated with mortality among patients with stroke and that a low heart rate is associated with a better functional outcome and less cognitive decline after an ischemic stroke.
PRoFESS was a 2x2 factorial trial that evaluated the safety and efficacy of aspirin and extended-release dipyridamole compared with clopidogrel (as noninferiority first then superiority), and the safety and efficacy of telmisartan compared with placebo (superiority) [Diener HC et al. Cerebrovasc Dis 2007]. The primary results of both comparisons have been previously published [Yusuf et al. N Engl J Med 2008; Sacco et al. N Engl J Med 2008].
Prior studies have shown an association between resting heart rate and cardiovascular (CV) events along the CV continuum, and stress models have shown that reducing heart rate may reduce the size of a stroke, explained Michael Böhm, MD, Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany, who presented the findings of the study. Thus, the current study was designed to answer the questions of whether baseline heart rate predicts recurrent stroke, myocardial infarction (MI), heart failure, or death after stroke or is associated with functional outcome or cognitive decline after recurrent stroke [Böhm M et al. Eur Heart J 2012].
The patients were grouped according to baseline heart rates, with quintiles of ≤64, 65 to 70, 71 to 76, 77 to 82, and >82 beats per minute (bpm). The predefined endpoints were disability after a recurrent stroke, as assessed with the modified Rankin Scale score and the Barthel Index, and cognitive function, as assessed with the Mini-Mental State Examination (MMSE) score. Disability was assessed at 3 weeks, and the MMSE score was determined at 4 weeks after randomization and at the penultimate visit.
Overall, increasing quartile of heart rate was associated with female gender and diabetes mellitus. b-blocker use, statin use, hypertension, and age were associated with lower heart rates.
All-cause mortality was higher among patients in the 3 highest quintiles of heart rate compared with the lowest quintile (71 to 76 bpm: HR, 1.32; 95% CI, 1.11 to 1.56; 77 to 82 bpm; HR, 1.42; 95% CI, 1.19 to 1.69; and >82 bpm: HR, 1.74; 95% CI, 1.48 to 2.06; p<0.0001 for both). Prof. Böhm noted that the heart rate threshold differed for CV and non-CV mortality (Figure 1). Baseline heart rate was not associated with MI, recurrent stroke, or new or worsening heart failure.
Figure 1. All-Cause Mortality, CV Death, and Non-CV Death According to Resting Heart Rate.
Reproduced with permission from the European Society of Cardiology. All rights reserved. Copyright © 2012.
Among 1627 patients who had a recurrent stroke, the functional outcome at 3 months was better in patients with a lower heart rate at baseline. The baseline heart rate was also significantly associated with cognitive decline according to the MMSE score (≤24 points; p=0.0001; Figure 2); more patients with a heart rate >82 bpm had a decrease of 2 points on the MMSE between the 1 month and penultimate visits.
Figure 2. Mini-Mental State Examination ≤24 Points.
Reproduced with permission from the European Society of Cardiology. All rights reserved. Copyright © 2012.
Prof. Böhm interpreted these findings as suggestive that lower heart rates may be associated with smaller strokes rather than fewer recurrent strokes. Further study will be needed to better understand whether heart rate plays a causative role in outcomes after stroke and whether therapies to reduce heart rate will be beneficial in patients experiencing a first stroke.
No clear evidence supports routine percutaneous coronary intervention (PCI) for patients with diabetes and multivessel disease, according to 5-year follow-up data from the Coronary Artery Revascularisation in Diabetes [CARDia; ISRCTN19872154] trial. Coronary artery bypass graft (CABG) surgery is favored, unless clinical features indicate that PCI is clearly preferable.
The CARDia trial was designed in the early 2000s as the first randomized comparison of PCI and CABG for patients with diabetes and multivessel (or complex disease of the left anterior descending) coronary artery disease [Kapur A et al. J Am Coll Cardiol 2010]. A total of 510 patients were randomized to CABG (n=254) or to PCI plus stenting and routine abciximab (n=256). The primary endpoint was a composite of all-cause mortality, myocardial infarction (MI), and stroke; the main secondary outcome included the addition of repeat revascularization to the primary outcome events. According to noninferiority analysis, PCI proved not to be noninferior to CABG at 1 year of follow-up (13.0% in the PCI group vs 10.5% in the CABG group; HR, 1.25; 95% CI, 0.75 to 2.09; p=0.39). The rates of all-cause mortality were similar for the 2 groups (3.2%).
Roger Hall, MD, Duke University, Durham, North Carolina, USA, reported the most recent findings of the trial. At a median of 5.1 years of follow-up, conventional intention-to-treat analysis did not show a significant difference in the primary endpoint for the 2 groups (26.6% in the PCI group vs 20.5% in the CABG group; HR,1.34; 95% CI, 0.94 to 1.93), but Dr. Hall said the study was underpowered for this comparison. PCI was associated with significantly higher rates of repeat revascularization (21.9% vs 8.3%; p<0.001), nonfatal MI (14% vs 6.3%; p=0.007), and a composite of death, MI, stroke, or repeat revascularization (37.5% vs 26%; p=0.005). There was no difference in nonfatal stroke (p=0.48). The similar all-cause mortality rates at 1 year continued at 5 years (14% in the PCI group and 12.6% in the CABG group; p=0.53; Table 1).
Table 1. Comparison of CABG and PCI at 5 Years of Follow-Up.
*Composite of death, nonfatal MI, or nonfatal stroke; CABG=coronary artery bypass graft; MI=myocardial infarction; PCI=percutaneous coronary intervention.
Dr. Hall noted that the findings did not confirm the results of other studies showing much higher mortality at 5 years in association with PCI, and thus, PCI may be an option in carefully selected patients with diabetes and multivessel disease as an alternative to CABG, although the latter remains the preferred method of revascularization for the majority of these patients.
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