22 Nov, 13 | by Alistair Lindsay
Long-term use of recommended cardiovascular (CV) risk modifying medications is low among patients at high-risk for CV events. Fixed-dose drug combination (FDC) therapy may reduce treatment gaps by lowering non-adherence, cost, complexity and therapeutic inertia. However, FDC may also reduce tailoring of individual medications and thereby lead to suboptimal risk control. The UMPIRE (Use of Multidrug Pill in Reducing Cardiovascular Events) randomized, open-label trial compared FDC versus usual care among individuals with high risk (>15% risk over 5 years) for CV disease and clear indications for aspirin, statin, and blood pressure lowering medications. A total of 2004 participants were randomized to FDC or usual care. Primary outcomes included change in self-reported adherence to all medications and changes in LDL and systolic blood pressure (SBP) from baseline. Overall, 88% of participants had established CAD. Median follow-up duration was 15 months. Patients treated with FDC has significantly improved adherence (RR 1.13, 95% CI 1.08 – 1.18) and change in SBP (-2.6 mm Hg, 95% CI -4.0 to -1.1 mmHg) and LDL (-4.2mg/dL, 95% CI -6.6 to -1.9 mg/dL). There were no significant differences in adverse events between the two groups.
Among patients at high-risk for CV events, use of FDC led to improved medication adherence and measures of CV risk compared to usual care. However, given that FDC was provided free of charge and usual care was not, it is uncertain how much of this effect simply reflects the cost of care. Future studies powered for CV events and accounting for cost differentials in therapy may further inform the role of FDC strategies for CV risk reduction.
- Thom S, Poulter N, Field J, et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA : the journal of the American Medical Association. Sep 4 2013;310(9):918-929.
22 Nov, 13 | by Alistair Lindsay
Acute pericarditis is a common self-limiting illness which usually has few sequelae. However, in a small proportion of patients, pericarditis can become recurrent making treatment more challenging. The use of colchicine to treat acute pericarditis and prevent recurrence has been a topic of increasing interest in recent years. In this multicentre, double-blind trial, adults with acute pericarditis were randomly assigned to receive either colchicine (at a dose of 500 mcg twice daily for 3 months for patients weighing >70 kg or 500 mcg once daily if ≤70 kg) or placebo in addition to conventional anti-inflammatory therapy (high dose aspirin or ibuprofen). A total of 240 patients diagnosed on clinical history, imaging and ECG criteria were randomised in a 1:1 fashion to either colchicine or placebo and followed for a median of 18 months. The primary outcome w, defined as incessant or recurrent pericarditis, occurred in 20 patients (16.7%) in the colchicine group and 45 patients (37.5%) in the placebo group (RR reduction in the colchicine group, 0.56; 95% CI, 0.30 to 0.72; NNT, 4; P<0.001). In addition to the primary outcome, benefits of colchicine therapy included a reduced rate of symptom persistence at 72 hours (19.2% vs. 40.0%, P=0.001), fewer recurrences per patient (0.21 vs. 0.52, P=0.001), a lower hospitalization rate (5.0% vs. 14.2%, P=0.02) and a higher remission rate at 1 week (85.0% vs. 58.3%, P<0.001). Adverse event rates were similar in the two study groups.
In patients with acute pericarditis, the addition of colchicine to conventional anti-inflammatory therapy significantly reduces symptom persistence and recurrent pericarditis. This well conducted trial confirms prior findings of nonrandomized and open label trials in support of colchicine for acute pericarditis.
- Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, Demarie D, Forno D, Ferro S, Maestroni S, Belli R, Trinchero R, Spodick DH and Adler Y. A Randomized Trial of Colchicine for Acute Pericarditis. N Engl J Med. 2013 Aug 31. [Epub ahead of print]
22 Nov, 13 | by Alistair Lindsay
In patients with ST-elevation myocardial infarction (STEMI), current guidelines support PCI of the infarct related artery and medical management of flow-limiting lesions in non-infarct related vessels (so-called bystander disease). This paradigm is challenged in the Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) study. In this single-blind trial performed at five UK centres, patients presenting with STEMI were randomly assigned to preventive PCI or no further PCI of non-infarct related vessels with >50% stenosis, immediately following reperfusion of the infarct related artery. The primary outcome was a composite of death from cardiac causes, nonfatal myocardial infarction, or refractory angina and the mean follow-up was 23 months. The trial was stopped early by the data and safety monitoring committee following enrolment of 465 out of a planned 600 patients due to a highly significant result favouring preventive PCI; the primary outcome occurred in 21 patients assigned to preventive PCI and in 53 patients assigned to no preventive PCI. This translates into an absolute risk reduction of 14% in the preventive PCI group (HR 0.35; 95% CI, 0.21 to 0.58; NNT 8; P<0.001). The hazard ratios were 0.34 (95% CI, 0.11 to 1.08) for death from cardiac causes, 0.32 (95% CI, 0.13 to 0.75) for nonfatal myocardial infarction, and 0.35 (95% CI, 0.18 to 0.69) for refractory angina. Although procedure times and contrast loads were significantly higher in the preventive PCI group, this did not translate into an increase in procedure-related adverse events.
In patients with STEMI and multivessel coronary artery disease undergoing infarct-artery PCI, preventive PCI of bystander lesions significantly reduced the risk of adverse cardiovascular events, as compared with PCI limited to the infarct artery. This important study contrasts directly with studies of PCI for stable CAD and suggests a different paradigm in the management of STEMI patients. Future investigation is needed to optimize the identification of true bystanders versus those lesions lying in wait in the setting of STEMI.
- Wald DS, Morris JK, Wald NJ, Chase AJ, Edwards RJ, Hughes LO, Berry C and Oldroyd KG. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013 Sep 19;369(12):1115-23.
3 Sep, 13 | by Alistair Lindsay
Patients with diabetes have more severe coronary disease at presentation and worse overall outcomes than their non-diabetic counterparts, even following surgical revascularisation. Whilst use of the left internal thoracic artery (LITA) is well established and improves event free survival when anastomosed to the LAD, the use of both right and left internal thoracic arteries in bilateral (BITA) grafting is less well described with concerns remaining over the associated increased risks of sternal wound infection, particularly in diabetics.
In this single-centre, retrospective, registry study, patients undergoing BITA grafting between 1996 and 2006 were studied. A total of 69 patients with insulin-treated diabetes and 732 with orally treated diabetes received isolated skeletonised BITA grafts. Of these patients, 338 were younger than 65 years, 322 were between 65 and 74 years old, and 141 were 75 years or older. Operative mortality was lower than logistic EuroSCORE-calculated mortality (2.9% vs 7%, P < 0.001). Predictors of increased mortality were critical preoperative state (P < 0.001) and age (P = 0.008).
There were 30 cases of sternal infection (3.7%); predictors were re-operation (P <0.001), peripheral vascular disease (P = 0.009), obesity (P = 0.012), chronic lung disease (P = 0.009), and female sex (P = 0.02). Although numbers were small, type 1 diabetics were also disproportionately prone to wound infection (7.2% in type 1 vs 3.2% in type II). Mean follow-up was 8.4 ± 4 years. Kaplan-Meier 10-year survivals were 75%, 59%, and 39% for patients younger than 65, 65 to 74, and at least 75 years, respectively (P <0.001). These were better than corresponding Charlson comorbidity index-predicted survivals (36%, 10%, and 3%, respectively; P <0.001). Off-pump surgery was independently associated with better long-term survival (P = 0.003).
BITA grafts are safe in patients with diabetes. Favourable short- and long-term outcomes outweigh increased sternal infection risk.
- Hemo E, Mohr R, Uretzky G, Katz G, Popovits N, Pevni D and Medalion B. Long-term outcomes of patients with diabetes receiving bilateral internal thoracic artery grafts. J Thorac Cardiovasc Surg. 2013 Sep;146(3):586-92.
3 Sep, 13 | by Alistair Lindsay
Pulmonary hypertension is associated with high morbidity and a poor prognosis. Medical therapies including PDE-5 inhibitors and ET-1 antagonists have led to symptomatic gains in carefully selected groups of patients, but the need for further developments remains apparent. Riociguat, the first in class of a new group which act as stimulators of soluble guanylate cyclase, was trialled in two simultaneously released studies: PATENT-1 investigating patients with primary pulmonary arterial hypertension and CHEST-1 investigating patients with chronic thromboembolic pulmonary hypertension.
PATENT-1 randomised 443 patients with symptomatic pulmonary arterial hypertension, who were either receiving no treatment or were receiving ET-1 antagonists or (nonintravenous) prostanoids, to receive placebo or riociguat in individually adjusted doses of up to 2.5 mg three times daily. The primary end point was change from baseline to week 12 in 6 minute walk distance. CHEST-1 randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to week 16 in 6 minute walk distance. Both studies also examined a number of secondary end points including the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnoea scale, quality-of-life variables, and safety.
Both studies produced highly statistically significant increases in their primary end-points (PATENT-1, a mean 30m increase (P<0.001) and CHEST-1, a mean 39m increase (P<0.001)) with achieved distance rising by 10-15% from baseline, a figure similar to the gains seen in the landmark PDE-5 and ET-1 trials. Similar highly significant changes were seen in secondary end-points in both studies with no common serious adverse events seen that were more common with the study drug than placebo.
In these two large double-blind placebo controlled studies, riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, offering a valuable new option for treatment in these conditions.
- Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D and Rubin LJ. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40.
- Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G and Wang C. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29.
14 Aug, 13 | by Alistair Lindsay
Nephrolithiasis (kidney stones) is an increasingly common condition occurring more frequently in men than women; over the last three decades the overall prevalence in the US population has risen to 8.8%. Links between nephrolithiasis and other systemic diseases have been noted, including subclinical atherosclerosis, hypertension, diabetes, metabolic syndrome, and cardiovascular disease. However, previous studies looking at the association between kidney stones and CHD have often not controlled for important risk factors and have shown inconsistent results.
This paper analysed the association between kidney stones and the risk of incident coronary heart disease (CHD) in three large prospective cohorts (Health Professionals Follow-up Study, Nurses’ Health Studies I and II). The diagnoses of nephrolithiasis and CHD were updated biennially during follow-up. The main outcome measure was the incidence of CHD, defined as fatal or nonfatal myocardial infarction or coronary revascularisation.
Of 242,105 patients participating in the study, 19,678 reported a history of kidney stones. Follow-up lasted up to 24 years in men and up to 18 years in women, over which period 16,838 incident cases occurred. After adjustment for potential confounders, women with a reported history of kidney stones had an increased risk of CHD than those without in two of the three cohorts (Nurses’ Health Studies I [Hazard Ratio 1.18] and II [Hazard Ratio, 1.48]), however there was no significant association seen in men.
This study found a modest, sex-specific increase in the risk of coronary heart disease in women with a history of kidney stones. The pathophysiological basis of this association requires further investigation.
- Ferraro PM, Taylor EN, Eisner BH, et al. History of Kidney Stones and the Risk of Coronary Heart Disease. JAMA 2013;310:408-415.
14 Aug, 13 | by Alistair Lindsay
Over the past three decades, obesity rates for adults have doubled and rates for adolescents have tripled. Therefore, younger people are experiencing a greater cumulative exposure to excess adiposity over their lifetime, however the long-term effects of this have been poorly studied to date. In particular, abdominal obesity is known to cause the development of atherosclerosis independent of overall adiposity, however no study has to date examined whether the duration of abdominal obesity contributes to the development or progression of atherosclerosis.
The CARDIA (Coronary Artery Risk Development in Young Adults) study initially enrolled 3275 adults aged 18 to 30 between 1985 and 1986; none had overall or abdomen obesity at baseline. Patients completed CT scanning for the presence of coronary artery calcium during 15-, 20-, or 25-year follow-up examinations. The duration of overall and abdominal obesity was also calculated using regular measurements of body mass index and waist circumference that were taken over the follow-up period.
Over the follow-up period, 40.4% patients developed overall obesity, and 41.0% of patients developed abdominal obesity. Rates of CAC per 1000 person-years were higher for those who experienced either form of obesity for more than twenty years, when compared to those who were not obese. Furthermore, 25.2% of patients with more than twenty years of overall obesity experienced progression of coronary artery calcium compared to 20.2% of patients with 0 years of obesity. Similarly, 27.2% of patients with more than twenty years of abdominal obesity showed progression of coronary disease compared to 19.5% of those with 0 years. After adjustment for body mass index or waist size, and other potential confounders, the hazard ratios for coronary calcium for each additional year of overall or abdominal obesity were 1.02 and 1.03, respectively.
A longer duration of both overall and abdominal obesity was associated with subclinical coronary artery disease and its progression through midlife, as measured by coronary artery calcium scoring.
- Reis JP, Loria CM, Lewis CE, et al. Association Between Duration of Overall and Abdominal Obesity Beginning in Young Adulthood and Coronary Artery Calcification in Middle Age. JAMA 2013;310:280-288.
15 Jul, 13 | by Alistair Lindsay
Only half of US adults have blood pressure levels that are controlled to recommended levels. Home blood pressure monitoring has previously been shown to be a useful adjunct to team-based care for hypertension, and home BP readings can predict cardiovascular risk more accurately than office BP measurements. Recent studies have suggested that a combined approach using telemedicine with nurse- or pharmacist-led care may be effective at improving blood pressure control, but these studies did not include follow-up.
In this randomised trial of 450 adults with uncontrolled BP in Minnesota, 12 months of intervention and 6 months of postintervention follow-up were performed. Patients from eight primary care clinics were randomised to provide usual care (n=222), and eight were randomised to provide a telemonitoring intervention (n=228). Intervention patients received home BP telemonitors and transmitted BP data to pharmacists who then adjusted antihypertensive pharmacotherapy accordingly. The main outcome measure was control of blood pressure to less than 140/90 (130/80 in patients with diabetes or chronic kidney disease) at six and twelve months.
The mean age of the 450 patients recruited was 61.1 years, with a mean systolic BP of 148mmHg and a mean diastolic of 85mmHg. 45% were female and 82% were white. When compared to patients in the usual care group, the mean change from baseline systolic BP was found to be lower in patients in the telemonitoring group at 6 (-10.7mm Hg),12 (-9.7mm Hg), and 18 (-6.6mm Hg) months follow-up (all P<0.05).
Telemonitoring of home BP, combined with pharmacist case management, led to better BP control than usual care during 12 months of intervention. The effects were seen to persist to 6 months of postintervention follow-up.
- Margolis L, Asche SE, Bergdall AR et al. Effect of Home Blood Pressure Telemonitoring and Pharmacist Management on Blood Pressure Control A Cluster Randomized Clinical Trial. JAMA 2013;310:46-56.
15 Jul, 13 | by Alistair Lindsay
There is a growing awareness in many fields of medicine that intestinal microbial organisms, collectively termed microbiota, play a crucial role in the global metabolism of their host. Recent animal studies have demonstrated mechanistic links between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). The relevance of this connection in humans is unknown but was investigated in two linked studies.
In the first, 40 healthy volunteers were recruited and levels of plasma and urinary TMAO were measured after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. In the second study, 4007 adults who were undergoing elective coronary angiography were recruited and followed for three years with a comparison made between baseline fasting plasma TMAO levels and incident major adverse cardiovascular events (death, myocardial infarction, or stroke). The results demonstrated a highly significant correlation between TMAO levels and the risk of a primary outcome event and also that circulating TMAO was modifiable by antibiotic therapy. In the healthy volunteer study, time-dependent increases in levels of both TMAO as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. In the coronary disease cohort study, increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (HR for highest vs. lowest TMAO quartile, 2.54; 95% CI, 1.96 to 3.28; P<0.001). In addition, an elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001).
The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events.
- Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013 Apr 25;368(17):1575-84.
15 Jul, 13 | by Alistair Lindsay
Right ventricular (RV) pacing is used in patients presenting with high degree atrioventricular block, both to relieve symptoms related to bradycardia and improve prognosis. The majority of these patients are elderly and many of them will have a degree of co-existing left ventricular dysfunction which may be exacerbated by the electrical and mechanical dyssynchrony that occurs with RV pacing. The large cardiac-resynchronization (CRT) pacing studies performed to date have systematically excluded patients with indications for standard bradycardia pacing devices so as to concentrate solely on the benefits derived from cardiac resynchronisation, and consequently there is a paucity of data regarding this group.
In this large multi-centre randomised controlled trial 691 patients were enrolled who had indications for pacing for high degree AV block and also had NYHA class I, II, or III heart failure, and a left ventricular ejection fraction of 50% or less (mean 40%). Patients received a CRT device (+/-cardioverter-defibrillator) and were randomly assigned to standard right ventricular pacing or biventricular pacing. The primary outcome was the time to death from any cause, an urgent care visit for heart failure that required intravenous therapy, or a 15% or more increase in the left ventricular end-systolic volume (LVESV) index. Patients were followed up for an average of 37 months and the outcome favoured biventricular pacing. The primary outcome occurred in 190 of 342 patients (55.6%) in the right-ventricular-pacing group, as compared with 160 of 349 (45.8%) in the biventricular-pacing group (HR, 0.74; 95% CI, 0.60 to 0.90) although it should be noted this was primarily driven by a change in LVESV index rather than a true clinical end-point. Results were similar in the pacemaker and ICD groups and left ventricular lead-related complications occurred in 6.4% of patients.
In this large industry-sponsored trial, biventricular pacing was superior to conventional right ventricular pacing in patients with high degree atrioventricular block and co-existing left ventricular systolic dysfunction.
- Curtis AB, Worley SJ, Adamson PB, Chung ES, Niazi I, Sherfesee L, Shinn T and Sutton MS. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med. 2013 Apr 25;368(17):1585-93.