Novel approaches in primary cardiovascular disease prevention: the HOPE-3 trial rationale, design, and participants' baseline characteristics

AbstractBACKGROUND:Cholesterol and blood pressure (BP) can be effectively and safely lowered with statin drugs and BP-lowering drugs, reducing major cardiovascular (CV) events by 20%-30% within 5 years in high-risk individuals. However, there are limited data in lower-risk populations. The Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial is evaluating whether cholesterol lowering with a statin drug, BP lowering with low doses of 2 antihypertensive agents, and their combination safely reduce major CV events in individuals at intermediate risk who have had no previous vascular events and have average cholesterol and BP levels.METHODS:A total of 12,705 women 65 years or older and men 55 years or older with at least 1 CV risk factor, no known CV disease, and without any clear indication or contraindication to the study drugs were randomized to rosuvastatin 10 mg/d or placebo and to candesartan/hydrochlorothiazide 16/12.5 mg/d or placebo (2 × 2 factorial design) and will be followed for a mean of 5.8 years. The coprimary study outcomes are the composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke and the composite of CV death, nonfatal MI, nonfatal stroke, resuscitated cardiac arrest, heart failure, and arterial revascularization.RESULTS:Participants were recruited from 21 countries in North America, South America, Europe, Asia, and Australia. Mean age at randomization was 66 years and 46% were women.CONCLUSIONS:The HOPE-3 trial will provide new information on cholesterol and BP lowering in intermediate-risk populations with average cholesterol and BP levels and is expected to inform approaches to primary prevention worldwide (HOPE-3 ClinicalTrials.govNCT00468923).

Rationale and design of INTERSTROKE: a global case-control study of risk factors for stroke.

UNLABELLED: Stroke is a major global health problem. It is the third leading cause of death and the leading cause of adult disability. INTERHEART, a global case-control study of acute myocardial infarction in 52 countries (29,972 participants), identified nine modifiable risk factors that accounted for >90% of population-attributable risk. However, traditional risk factors (e.g. hypertension, cholesterol) appear to exert contrasting risks for stroke compared with coronary heart disease, and the etiology of stroke is far more heterogeneous. In addition, our knowledge of risk factors for stroke in low-income countries is inadequate, where a very large burden of stroke occurs. Accordingly, a similar epidemiological study is required for stroke, to inform effective population-based strategies to reduce the risk of stroke. METHODS: INTERSTROKE is an international, multicenter case-control study. Cases are patients with a first stroke within 72 h of hospital presentation in whom CT or MRI is performed. Proxy respondents are used for cases unable to communicate. Etiological and topographical stroke subtype is documented for all cases. Controls are hospital- and community-based, matched for gender, ethnicity and age (+/-5 years). A questionnaire (cases and controls) is used to acquire information on known and proposed risk factors for stroke. Cardiovascular (e.g. blood pressure) and anthropometric (e.g. waist-to-hip ratio) measurements are obtained at the time of interview. Nonfasting blood samples and random urine samples are obtained from cases and controls. Study Significance: An effective global strategy to reduce the risk of stroke mandates systematic measurement of the contribution of the major vascular risk factors within defined ethnic groups and geographical locations.

Do patients with heart failure appropriately undergo invasive procedures post-myocardial infarction? Results from a prospective multicentre study.

BACKGROUND: The degree of adherence to guideline recommendations that patients following myocardial infarction (MI) with congestive heart failure (CHF) undergo early angiography, and angioplasty if indicated, is unknown. METHODS: We prospectively evaluated the use of invasive procedures in patients with segment-elevation myocardial infarction (STEMI), non-STEMI and CHF, admitted in 1 month to 16 Australian hospitals. RESULTS: Of 475 post-MI patients (248 (52.2%) with STEMI), 112 (23.6%) had CHF, (57 (23.0%) with STEMI). Patients with CHF, compared with those without CHF, were older (67.8 vs 63.2 years; P = 0.002) and were more often women (34 vs 24%, P = 0.03), but had similar rates of other risk factors. Compared with post-MI patients without CHF, patients with CHF had fewer invasive procedures: angiography 72.3% versus 85.1% (P = 0.002) and angioplasty 33.9% versus 52.9% (P < 0.001) (12 (2.5%) patients underwent coronary surgery in-hospital); and among STEMI patients (angiography 72.3% CHF vs 89.5% no CHF [P < 0.001]; angioplasty 50.9% CHF vs 69.1% no CHF [P = 0.011]); these differences remained significant after adjustment for clinical covariates. Of the 121 (25.5%) post-MI patients aged > or =75 years, compared with those <75 years, the frequencies of angiography and angioplasty procedures were 66.1% versus 87.6% (P < 0.001) and 33.9% versus 53.4% (P < 0.001), respectively; 66% of the elderly with, and without, CHF had angiography. CONCLUSION: The presence of CHF post-MI resulted in lower rates of use of angiography and angioplasty, which was not explained by lower procedure rates in the elderly. As these guideline-recommended procedures may improve survival in patients with CHF post-MI, future strategies should aim to enhance their use.

The Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry in patients with unstable angina.

Clinical approaches to the prevention of the potentially catastrophic consequences of coronary ischemic phenomena such as unstable angina and suspected non-Q-wave myocardial infarction (MI) differ across the world. In addition to prevailing physician beliefs in different societies, the level of access to catheterization laboratories largely determines whether an interventionist or conservative strategy is adopted. The Organization to Assess Strategies for Ischemic Syndromes (OASIS)--a prospective registry of approximately 8,000 patients with acute myocardial ischemia with no ST elevation, treated in 95 hospitals across 6 countries--furnished a unique window into regional differences in clinical management and the frequency and timing of invasive procedures (i.e., angiography, percutaneous transluminal coronary angioplasty [PTCA], and coronary artery bypass graft [CABG] surgery), as well as the outcomes of these trends. At 6 months after symptom onset, patients in the United States and Brazil, where the catheterization laboratory facilities are more accessible, underwent significantly (p <0.001) more angiography (69.4%), PTCA (23.6%), and CABG (25.2%) than in Canada and Australia, where the corresponding rates were 48.4%, 17.0%, and 16.8% (p <0.001), respectively; and in Hungary and Poland, where the respective rates were 23.5%, 5.8%, and 10.9% (p <0.001). This relatively aggressive approach led at 6 months to a more substantial decrease in refractory angina in the United States and Brazil than in Canada and Australia (20.4% vs 13.9%; p <0.001), but no improvement in rates of cardiovascular mortality and MI (10.5% versus 10.5%; p = 0.36). There was a significant (p < or = 0.012) increase in stroke, (1.9% vs 1.3%; p = 0.010) and major bleeding (1.9% vs 1.1%; p = 0.009) events. Furthermore, an inverse correlation emerged between baseline cardiovascular risk status and frequency of angiography and PTCA interventions preferentially for low-risk compared with high-risk patients. In concert with findings from other recent randomized trials, the OASIS Registry data suggest that although there are fewer hospital readmissions for unstable angina, there is a trend toward increased rates of death, MI, and stroke. These data urge a cautious approach to the use of invasive procedures in patients with unstable angina unless future trials demonstrate a clear benefit with an aggressive approach.

Immunogenicity and reactogenicity associated with an 18-month booster dose of a new diphtheria-tetanus-whole cell pertussis vaccine.

OBJECTIVE: To establish safety and immunogenicity of a reformulated whole cell pertussis based diphtheria-tetanus-pertussis vaccine (DTPw) at the 18-month booster stage following a 2, 4, and 6-month primary immunization course. METHOD: Open trial in suburban Melbourne in 100 healthy children initially recruited through maternal and child health centres. Thirty-five subjects were bled prior to vaccination, and 4-6 weeks after vaccination. A 7-day diary card was used to record subject temperatures and other systemic and local clinical signs. RESULTS: The increase in antibody geometric mean titres (GMT) after boosting was 19.5-fold (95%ci 14.2, 27.2) for tetanus and 26.5-fold (95%ci 16.6, 42.4) for diphtheria. Pertussis antibody GMTs also all showed substantial increases following the booster, with mean fold changes in titre ranging from 7.3 (Agg2) to 31.3 (Fha). Seventeen percent of subjects (95%ci 10%, 26%) experienced axillary temperatures > or = 38 degrees C during the 24-h period following vaccination. Low rates of significant (> 25 mm) injection site redness (13%) and swelling (8%) were recorded at 24 h postvaccination. CONCLUSION: This vaccine was well tolerated by children at 18 months of age, and showed substantial boosting of antibody to all components.

Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators.

BACKGROUND: There are wide variations between countries in the use of invasive cardiac catheterisation and revascularisation procedures for patients with acute ischaemic syndromes. We studied the relation between rates of such procedures and rates of cardiovascular death, myocardial infarction, stroke, refractory angina, and major bleeding in a prospective, registry-based study in six countries with widely varying intervention rates. METHODS: 7987 consecutive patients presenting with unstable angina or suspected myocardial infarction without ST-segment elevation were recruited prospectively from 95 hospitals in six countries and followed up for 6 months. FINDINGS: The rates of all procedures were highest in patients in Brazil and the USA, intermediate in Canada and Australia, and lowest in Hungary and Poland. There were no significant differences in rates of cardiovascular death or myocardial infarction among these countries (4.7% overall [range 3.7-5.6] at 7 days; 11% overall [9-12] at 6 months). For the countries with the highest rates of invasive procedures (59%) versus the rest (21%) there was no difference in rate of cardiovascular death or myocardial infarction (adjusted odds ratio 0.88 at 7 days and 1.0 at 6 months). Rates of stroke were higher in Brazil and the USA than in the countries with lower intervention rates (adjusted odds ratio at 7 days 3.0, p=0.012; at 6 months 1.8, p=0.004) but rates of refractory angina at 7 days (0.7, p<0.001) and readmission for unstable angina at 6 months were lower (0.70, 0.63; both p<0.001). Comparison of results for hospitals without cardiac-catheterisation facilities and for those with such facilities gave adjusted odds ratios for cardiovascular death, myocardial infarction, or stroke at 6 months of 0.83 (10.6% vs 12.5%, p=0.05) and for refractory angina of 1.25 (19.3% vs 16.1%, p=0.09). INTERPRETATION: Higher rates of invasive and revascularisation procedures were associated with lower rates of refractory angina or readmission for unstable angina, no apparent reduction in cardiovascular death or myocardial infarction, but with higher rates of stroke. Randomised trials should assess the relative impact of conservative and more aggressive approaches to invasive cardiac procedures and revascularisations in patients with unstable angina.

Primary course immunogenicity and reactogenicity of a new diphtheria-tetanus-whole cell pertussis vaccine (DTPw).

OBJECTIVE: To establish safety, immunogenicity, and batch stability of a reformulated whole cell pertussis based diphtheriatetanus-whole cell pertussis (DTP) vaccine (nDTPw) compared to the currently marketed Australian DTPw vaccine (Triple Antigen) in a three dose 2, 4 and 6 month primary immunization course. Reformulation was necessary to make the DTPw vaccine suitable for combination with hepatitis B and Haemophilus influenzae b vaccines. METHODS: Double blind randomized controlled trial in suburban Melbourne in 812 healthy infants recruited through maternal and child health centres, of whom 208 received Triple Antigen and 604 received nDTPw. RESULTS: Results for both reactogenicity and immunogenicity were similar and were not significantly different for the three batches of nDTPw. No new, serious, or unexpected adverse effect was recorded. Nearly twice as many nDTPw infants experienced no general reaction to the third dose (18%) compared to Triple Antigen (11%, P = 0.06). An elevated temperature (> or = 38 degrees C axillary) occurred in about three out of 10 babies overall, with rates being slightly higher for both vaccines after the second vaccination. Local reaction rates were significantly less common for nDTPw on days 2 and 3 following each of the three vaccinations. After dose three, 30% of nDTPw subjects experienced no local reaction compared to 20% of Triple Antigen subjects (P = 0.015, 95% Cl on difference 2%, 19%). Swelling after doses one and three occurred in 30% and 24% of Triple Antigen subjects, compared to 23% (P = 0.07, 95% Cl diff 0%, 13%) and 14% (P = 0.017, 95% Cl diff 2%, 17%) of nDTPw subjects. Tenderness after doses two and three occurred in 80%, and 78% of Triple Antigen subjects, compared to 71% (P = 0.04, 95% Cl diff 1%, 17%) and 68% (P = 0.025, 95% Cl diff 2%, 19%) of nDTPw subjects. There was a significantly higher post immunization diphtheria antitoxin GMT (2.73 IU/mL) for Triple Antigen compared to nDTPw (1.89 IU/mL; P = 0.02), although no subject in either vaccine group had a tetanus or diphtheria antibody titre less than six times the protective level of 0.01 IU/mL following immunization. The nDTPw post immunization GMTs were significantly higher for Agg2, Fha, and pertactin compared to Triple Antigen geometric mean titres (GMTs). CONCLUSION: nDTPw is a safe and immunogenic vaccine when compared to Triple Antigen. The reformulated vaccine is an acceptable replacement for the currently marketed formulation, and for evaluation as a component of future combination vaccines.