Secondary Prevention Population Research Articles

A Systematic Review of Cardiovascular Outcomes-Based Cost-Effectiveness Analyses of Lipid-Lowering Therapies.

Previous reviews have evaluated economic analyses of lipid-lowering therapies using lipid levels as surrogate markers for cardiovascular disease. However, drug approval and health technology assessment agencies have stressed that surrogates should only be used in the absence of clinical endpoints. The aim of this systematic review was to identify and summarise the methodologies, weaknesses and strengths of economic models based on atherosclerotic cardiovascular disease event rates. Cost-effectiveness evaluations of lipid-lowering therapies using cardiovascular event rates in adults with hyperlipidaemia were sought in Medline, Embase, Medline In-Process, PubMed and NHS EED and conference proceedings. Search results were independently screened, extracted and quality checked by two reviewers. Searches until February 2016 retrieved 3443 records, from which 26 studies (29 publications) were selected. Twenty-two studies evaluated secondary prevention (four also assessed primary prevention), two considered only primary prevention and two included mixed primary and secondary prevention populations. Most studies (18) based treatment-effect estimates on single trials, although more recent evaluations deployed meta-analyses (5/10 over the last 10years). Markov models (14 studies) were most commonly used and only one study employed discrete event simulation. Models varied particularly in terms of health states and treatment-effect duration. No studies used a systematic review to obtain utilities. Most studies took a healthcare perspective (21/26) and sourced resource use from key trials instead of local data. Overall, reporting quality was suboptimal. This review reveals methodological changes over time, but reporting weaknesses remain, particularly with respect to transparency of model reporting.

Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population.

Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%-28%), varying from <10% in 18% to >30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be <10% in 47% and >30% in 9% of the patients (median, 11%; interquartile range, 7%-17%). Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.

The relationship between Lp(a) and CVD outcomes: a systematic review.

Robust associations between lipoprotein(a) [Lp(a)] and CVD outcomes among general populations have been published in previous studies. However, associations in high risk primary prevention and secondary prevention populations are less well defined. In order to investigate this further, a systematic review was performed including prospective studies, which assessed the relationship between Lp(a) and CVD outcomes using multivariable analyses. Additional information was gathered on Lp(a) assays, multivariable modelling and population characteristics.Literature searches from inception up to December 2015 retrieved 2850 records. From these 60 studies were included. Across 39 primary prevention studies in the general population (hazard ratios ranged from 1.16 to 2.97) and seven high risk primary prevention studies (hazard ratios ranged from 1.01 to 3.7), there was evidence of a statistically significant relationship between increased Lp(a) and an increased risk of future CVD. Results in 14 studies of secondary prevention populations were also suggestive of a modest statistically significant relationship (hazard ratios ranged from 0.75 to 3.7).Therefore current evidence would suggest that increased Lp(a) levels are associated with modest increases in the risk of future CVD events in both general and higher risk populations. However, further studies are required to confirm these findings.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0258-8) contains supplementary material, which is available to authorized users.

Abstract P307: The Impact of Aspirin Primary Prevention Treatment Guidelines, 2007-2015: Aspirin Use Stratified by Cardiovascular Disease Risk

Background: Current national cardiovascular disease primary prevention (PP) guidelines recommend low dose aspirin (ASA) to prevent a first heart attack or stroke in appropriate candidates. The 2009 United States Preventive Services Task Force (USPSTF) ASA primary prevention recommendation was not widely implemented, and minimal data exist to define the efficacy of this “A” level recommendation. This study was designed to evaluate the impact of this recommendation on PP ASA use in primary care clinics in a large, regional health system over a 9 year period (2007-2015) stratifying patients by their 10 year global risk for a primary ischemic event. Methods: Bi-annual, cross-sectional electronic medical record (EMR) data were collected from 2007 to 2015 to evaluate documented ASA use for all office-based encounters involving a primary care provider within the Fairview Health System (Minnesota). PP candidates were defined as individuals within the USPSTF guideline target population (men ages 45-79 and women ages 55-79 years) with no documented history of an atherosclerotic syndrome. Appropriate ASA use candidates were defined as PP individuals with no ASA use contraindications (peptic ulcer disease, gastrointestinal bleeding or use of other antithrombotic medications). Ten year cardiovascular disease (CVD) risk was calculated using the ACC/AHA 2013 global risk calculator. ASA use was evaluated bi-annually in the total PP population and a stratified subset characterized by &lt;10%, 10-20% and &gt;20% ten year risk of an ischemic event. Secondary prevention (SP) ASA use was assessed as a reference standard for ideal penetration of guideline recommended ASA use. Results: Over 270,000 unique encounters were evaluated over the 9 year study period. Of those, 88,055 were PP ASA candidates with data for risk score calculation. Appropriate PP ASA use rates did not improve throughout the study period, with an average of 43% PP ASA use compared to 77% in the SP population. When stratified by &lt;10%, 10-20% and &gt;20% ten year CVD risk, average appropriate PP ASA use was 41%, 63% and 73% respectively, representing an absolute difference of 36%, 14% and 4% respectively compared to SP ASA use. Appropriate PP ASA use did not increase in any risk category following the publication of the 2009 USPSTF guidelines. Documented contraindications to ASA use were very low (6%) in the PP population. Conclusion: Appropriate PP ASA use in primary care settings increases as CVD risk increases. PP ASA use in the highest risk population is similar to the rate in the SP cohort. A large primary prevention aspirin treatment gap exists in the medium and low CVD risk categories. Publication of the 2009 USPSTF recommendation was not associated with improved aspirin use in any risk category. Public health interventions to safely and effectively disseminate this PP ASA recommendation, involving both the public and health care providers, are warranted.

Abstract 18909: Interaction Between a Novel Protein Glycan Derived Inflammation Biomarker (GlycA) and HDL Particle Subclasses on Mortality in a Cardiac Catheterization Cohort

Background: GlycA, a novel serum inflammatory biomarker composed of enzymatically glycosylated acute phase proteins, is associated with cardiovascular events in a primary prevention population. Emerging data suggest that inflammation may adversely impact HDL function. We sought to define the role of GlycA as a biomarker of adverse events in a secondary prevention population and to understand potential interactions between GlycA and HDL subclasses. Methods: GlycA and medium and small HDL particles (MS-HDL) were measured with NMR spectroscopy in 7,617 individuals in the CATHGEN biorepository. Cox proportional hazards modeling was used to test the relationship of GlycA, MS-HDL and the GlycA*MS-HDL interaction term with time-to-death in multivariable models adjusted for 11 CV risk factors and stratified by diabetes status. We then assessed the ability of GlycA, MS-HDL, and GlycA*MS-HDL to improve risk discrimination in clinical models. Results: Over a mean time-to-event of 2547 days, 2318 individuals died. Higher GlycA levels were associated with increased risk of death (HR 1.34 [1.29-1.39], p&lt;0.0001). In diabetes-stratified models, the greatest quartile of GlycA in patients without diabetes conferred greater risk of mortality than the lowest quartile of GlycA in patients with diabetes. In models containing MS-HDL (main effect HR 0.69 [0.66-0.72], p&lt;0.0001), addition of GlycA (HR 1.28 [1.24-1.32], p&lt;0.0001) and GlycA*MS-HDL (p&lt;0.0001) demonstrated independent associations of these variables with mortality. MS-HDL levels were associated with lower mortality risk at lower GlycA levels but with increased mortality risk at greater GlycA levels. There was an increasing improvement of model fit characteristics with incremental addition of GlycA, MS-HDL and GlycA*MS-HDL to robust clinical models. Conclusion: GlycA is associated with an increased risk of mortality in a secondary prevention population. The interaction of GlycA with MS-HDL suggests that greater systemic inflammation can modify the association of HDL subclasses with clinical outcomes and at the highest levels of GlycA, may reverse the protective effect of HDL. These findings have implications for the interpretation of diagnostic and therapeutic tools involving HDL measurements.

Abstract 18114: Differences Between Observed and Predicted Cardiovascular Event Rates Using the Framingham and REACH Equations: The Case of High-intensity Statin Users in the United Kingdom

Background: High-intensity statin users are a select group of patients, and their observed cardiovascular (CV) event risk may not align with the predicted risk from published risk equations. Hypothesis: Published risk equations accurately characterize the observed patient risk in high intensity statin users Methods: Five cohorts were studied in the Clinical Practice Research Datalink: high-risk primary prevention (HRPP - prevalent diabetes in the absence of any other CV event), evident CV disease (ECVD - prevalent stable angina, revascularization, transient ischemic attack, carotid stenosis, abdominal aortic aneurysm, or peripheral vascular disease), incident acute coronary syndrome (ACS), incident ischemic stroke (IS), and incident heart failure (HF). Patients were followed from 1/1/2005 (HRPP, ECVD) or first qualifying event (ACS/IS/HF) until the first CV hospitalization after cohort inclusion, death, or end of observation (December 31, 2011). Predicted 10-year overall risk was based on Framingham (D’Agostino 2008) for HRPP and on REACH (Wilson, 2012) for all other cohorts. Acute (&lt;=12 mos) and long-term rates (12+ mos) were generated for recurrent events in the ACS, IS, and HF groups (Wilson, 2012). Predicted rates were compared to the observed event rates using rate ratios, (observed rate/predicted rate). Standard errors were estimated using Poisson regression. Results: Framingham was well calibrated to the observed event rate in the HRPP cohort (RR 0.92 (95% CI 0.87 to 0.97). For all secondary prevention cohorts, REACH consistently underestimated the observed event rate, though the magnitude of the difference varied (see Table 1). Conclusions: Traditional risk scores consistently underestimated event rates in all secondary prevention populations treated with a high intensity statin. Observed events are vital for anchoring predicted rates to accurately determine country level estimates in certain patient populations.

Abstract 243: A Novel Cost Effectiveness Model of Eicosapentaenoic Acid (EPA) for Secondary Prevention in the United States

Background: Cardiovascular disease (CVD) is responsible for one in every four deaths in the United States as well as direct and indirect costs exceeding $100 billion. Each year in the US, 210,000 heart attacks and 185,000 strokes occur among patients who have previously experienced one. Given the substantial burden of CVD, a novel model was developed to explore the cost-effectiveness of a prescription EPA only omega-3 intervention among secondary prevention populations in the US. Methods: The framework and initial clinical data source for model input was the published Japanese EPA Lipid Intervention Study (JELIS) secondary prevention strata, which included major coronary and stroke endpoints. Two US-focused base case scenarios were developed based on published data: a standard and an aggressive scenario, with the aggressive scenario assuming a highly effective intervention. Costs and utilities were derived from published studies in the US, or the wholesale acquisition cost (WAC), in the case of prescription costs. The initial utility value assigned to this secondary prevention population was 0.78, with unique decrements for each event. Expert opinion was used when clinical assumptions were required for unreported data points. The model takes the perspective of a US, commercial, third-party payer. Costs are presented in 2014 US$. The model extends for 5 years and applies a discount rate of 3% to costs and benefits. Sensitivity analyses are presented to understand the influence of various parameters on outcomes. Results: Under the base case assumptions for the standard US scenario, EPA plus statins compared to statins alone was associated with cost savings (average 5-year costs $29,393 vs. $30,587 per person for EPA plus statins vs statins monotherapy, respectively) and improved utilities (average 3.61 vs. 3.56 respectively), denoting that the strategy of combining EPA with statin therapy exceeds accepted thresholds for cost-effectiveness when compared to statin monotherapy. The aggressive scenario was even more favorable for the combined strategy; being more cost-effective than statin monotherapy, with five-year savings ($29,707 vs. $38,793) and more utilities accrued (3.61 vs 3.50). The results of this model were found to be robust during sensitivity analyses exploring alternative scenarios, with consistent findings of cost-effectiveness or cost savings in the standard and aggressive US scenarios. Conclusions: This novel model suggests that combining EPA with statin therapy for secondary prevention of cardiovascular disease in the United States may be cost-saving and appears to be a more compelling intervention than statin monotherapy. The framework of this model provides a starting point for development of microsimulation models as more data become available.

Impact of Switching From High-Efficacy Lipid-Lowering Therapies to Generic Simvastatin on LDL-C Levels and LDL-C Goal Attainment Among High-Risk Primary and Secondary Prevention Populations in the United Kingdom

PurposeHigh cholesterol, especially high low-density lipoprotein cholesterol (LDL-C), is an important risk factor for cardiovascular disease (CVD) morbidity/mortality. Switching from high-efficacy lipid-lowering therapies (HETs) to simvastatin might lead to sub-optimal control of LDL-C. Our objective was to evaluate the impact of switching from HETs to generic simvastatin on LDL-C levels and LDL-C goal attainment among the high-risk primary and secondary prevention populations in the United Kingdom. MethodsThis retrospective cohort study was conducted using Clinical Practice Research Datalink database. Included were individuals with more than 2 months of prescriptions of the following HETs between August 1, 2004 and December 31, 2008: simvastatin/ezetimibe fixed dose (S/E), simvastatin and ezetimibe co-administration (S+E), atorvastatin and ezetimibe co-administration (A+E), rosuvastatin and ezetimibe co-administration (R+E), rosuvastatin monotherapy, and atorvastatin monotherapy. For each baseline HET, we used analysis of covariance (ANCOVA) to estimate the least squares mean (LSM) difference in the percentage change from baseline in LDL-C between switchers and non-switchers, and logistic regression to estimate the odds ratio of attaining the LDL-C goal (<3 mmol/L for primary prevention and <2 mmol/L for secondary prevention, by JBS2) at follow-up. Propensity score adjusted analyses were conducted to reduce selection bias. Findings30,148 patients met the eligibility criteria with 83.8% received atorvastatin, 9.5% rosuvastatin and 2.6% S/E and S+E combined. 89.1% of patients switching from atorvastatin switched to an equivalent or higher dose of simvastatin (dose equivalency was determined by relative efficacy of one statin to other statins), while 100% of those switching from simvastatin/ezetimibe and 96.8% of those switching from rosuvastatin switched to lower than equivalent dose of simvastatin. Compared to non-switchers, the adjusted least squares mean differences in the percentage change in LDL-C levels from baseline were 18.74% (p = 0.0003), 16.73% (p < 0.0001), and −0.11% (p = 0.9044) when switching from simvastatin/ezetimibe, rosuvastatin, and atorvastatin, respectively. The odds of LDL-C goal attainment at follow-up among switchers from simvastatin/ezetimibe, rosuvastatin, and atorvastatin were 0.40 (95% CI: 0.23–0.70), 0.36 (95% CI: 0.26–0.51) and 1.03 (95% CI: 0.92–1.15) relative to non-switchers respectively. ImplicationsAmong the high risk CVD population in UK, switching to simvastatin from HET, especially rosuvastatin and simvastatin/ezetimibe, resulted in an increase in LDL-C levels and lower goal attainment. These historical data reinforce the appropriateness of the changes in the new Joint British Guideline (JBS3) which no longer recommends starting simvastatin 40 mg.

Abstract 14994: How Low Should You Go in Secondary Prevention Treatment of LDL Cholesterol: Observational Insights from the Intermountain Heart Collaborative Study

Introduction: Epidemiologic studies have identified high LDL cholesterol levels as an independent risk factor for cardiovascular (CV) disease, and randomized trials with statin therapy have demonstrated added clinical benefit when LDL levels are reduced to at least 70 mg/dL. However, whether targeting significantly lower secondary prevention LDL levels is beneficial, or perhaps actually may be unsafe, is not known. Methods: Patients undergoing coronary angiography who were documented to have significant (≥50% stenosis) coronary artery disease (CAD), discharged on statin therapy with an LDL level &lt;100 mg/dL and had ≤3y clinical follow-up were studied. Patients were stratified, according to on-statin LDL levels, into ultra low (&lt;40 mg/dL [n=221]), very low (40-69 mg/dL [n=1,684]) and low (70-99 mg/dL [n=3,317]) categories and followed for the long-term endpoints of all-cause death, cardiac death, non-cardiac death, MI, stroke, coronary revascularization (CR) and MACE (death, MI, stroke, CR). Hazard ratios (HRs) comparing the three LDL groups were calculated by Cox regression, adjusting for 17 baseline variables. Results: A total of 5,222 patients (age = 66±12 yrs, men = 72%, hypertension = 69%, diabetes = 30%, smokers = 29%, ACS presentation = 69%) were studied. Follow-up for the ultra low, very low and low LDL categories was 6.1±4.3, 6.4±3.9 and 7.3±4.1 yrs respectively. Event rates and adjusted HRs are shown in the Table. Conclusions: In a large secondary prevention population with significant CAD on statin therapy, treating LDL cholesterol levels to &lt;70 mg/dL compared to 70-99 mg/dL was not associated with superior long-term CV outcomes. From a non-CV standpoint, LDL levels down to 40 mg/dL appeared to be safe, but ultra low LDL levels (&lt;40 mg/dL) were associated with a significantly increased risk of non-CV death. Based on this information, very aggressive secondary prevention treatment of LDL cholesterol to levels below 40 mg/dL may require further study.

Abstract 385: The Impact of Aspirin Primary Prevention Treatment Guidelines: Temporal Trends in Aspirin Use for Primary vs Secondary Prevention, 2005-2013

Background: Current national prevention guidelines recommend use of low dose aspirin (ASA) for both the primary prevention (PP) and secondary prevention (SP) of heart attack and stroke. ASA use for SP has been documented to have increased over the past decade. Since the publication of the 2009 United States Preventative Services Task Force (USPSTF) recommendations for PP ASA use, data describing the trends in PP ASA use in primary care are sparse. This study evaluates trends in PP and SP ASA use in primary care clinics from a large, regional health system over an 8 year period (2005-2013). Methods: A bi-annual cross-sectional electronic medical record (EMR) chart extraction was performed from 2005 to 2013 to evaluate documented ASA use for all patient encounters within primary care clinics in the Fairview Health System (Minnesota). Primary prevention candidates were defined as individuals within the USPSTF guideline age and sex target populations (men aged 45-79, and women aged 55-79 years) with no documented history of an atherosclerotic syndrome or contraindication to ASA use (aspirin allergy, peptic ulcer disease, or concurrent antithrombotic therapy). Secondary prevention candidates were defined as adults within the same age and gender range with a history of coronary artery disease, peripheral artery disease or ischemic stroke. The ASA treatment to candidacy ratio was calculated for the PP and SP populations. Results: Over 225,000 unique encounters at 66 primary care clinics were analyzed over the 8 year study period. The PP population was younger (60.4±8.7 vs. 66.2±8.3 years), with lower prevalence of hypertension (49 vs. 79%), hyperlipidemia (54 vs. 84%), and diabetes (17 vs. 35%) compared to the SP cohort. The mean SP ASA use of 86% was high, concordant with national trends, and did not change over this period. In contrast, PP ASA average use was 44% with no increase after publication of the 2009 USPSTF guideline. Documented contraindications to ASA use were uncommon (ASA allergy, 2.1 and 2.8%; peptic ulcer disease, 3.2 and 7.2%; and use of other antithrombotic medications, 4.6 and 32.6% in PP and SP populations respectively). Conclusion: Secondary prevention ASA use in primary care settings remains high, but ASA use for primary prevention of cardiovascular events is low. Despite creation of national guidelines, aspirin use in the PP population is half the rate of ASA use for secondary prevention. Additional methods to safely and effectively disseminate this primary prevention aspirin use recommendation, targeting both the public and health care providers, are warranted.

Improving adherence to lipid-lowering therapy in a community pharmacy intervention program: a cost-effectiveness analysis.

Pharmaceutical care in community pharmacies has been shown to improve adherence to chronic therapies. Long-term impact on clinical outcomes or medical cost savings, however, remains understudied. To estimate the cost-effectiveness of a pharmaceutical care intervention program in Dutch community pharmacies that improved patients' adherence to lipid-lowering therapy. An economic evaluation was performed using a time-dependent Markov model from the health care payer perspective. Participants were patients initiating lipid-lowering therapy for primary prevention (40%) or secondary prevention (60%) of cardiovascular events (CVEs). The intervention was the pharmaceutical care program MeMO (Medication Monitoring and Optimisation) in 9 community pharmacies in the Netherlands, based on continuous monitoring and optimization of lipid-lowering therapy in new patients. The follow-up period of the program was 1 year. The main outcome of the intervention program was discontinuation of lipid-lowering therapy. This outcome was extrapolated in the economic model to lifelong costs, quality of life, reductions in cardiovascular events, and incremental cost-effectiveness ratios. Patients in the MeMO program had a lower risk for therapy discontinuation, RR = 0.49 (0.37 to 0.66); the effectiveness was similar in primary and secondary prevention. In a cohort of 1,000 primary and secondary prevention patients, the MeMO program resulted in a reduction of 7 nonfatal strokes, 2 fatal strokes, 16 nonfatal myocardial infarctions (MIs), 7 fatal MIs, and 16 revascularizations over patients' lifetime. Additional medication, disease management, and intervention costs in the MeMO program were €411,000; the cost savings due to reduced CVEs were €443,000. The MeMO program resulted in 84 quality-adjusted life-years (QALYs) gained and net cost savings of €32,000. Clinical benefits and cost savings were highest in the secondary prevention population. Pharmaceutical care in community pharmacies can improve statin therapy adherence, resulting in better prevention of CVEs. The MeMO program resulted in considerable clinical benefits and net cost savings. Programs by community pharmacies targeted at improving adherence may provide good value for money, and health care insurers should consider reimbursing these activities.

Adverse events following implantable cardioverter defibrillator implantation: a systematic review.

Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death, but patients need to be counseled about potential harms. We summarized the evidence on adverse events from ICDs with a focus on ICD use for primary prevention of sudden cardiac death. We searched MEDLINE and Cochrane Central Register of Controlled Trials from 2002 through 2012 for reports of adverse events from ICDs implanted for primary prevention or mixed indications (primary and secondary prevention). Studies had to have ≥500 patients and specify patient numerators and denominators. Data from 35 independent cohorts reported in 53 articles were included. Reports from one registry provided high quality evidence on adverse events during hospitalization for ICD implantation. Adverse events ranged from 2.8 to 3.6%. Serious adverse events ranged from 1.2 to 1.4%. The most frequent serious adverse events were pneumothorax (0.4-0.5%) and cardiac arrest (0.3%). The quality of the evidence for long-term adverse events was low. Frequency of adverse events post-hospitalization was variable, as was follow-up: device-related complications <0.1-6.4% (2-49 months), lead-related complications <0.1-3.9% (1.5-40 months), infection 0.2-3.7% (1.5-49 months), and thrombosis 0.2-2.9% (1.5-49 months). Evidence for inappropriate shock was of moderate quality with 3-21% of patients experiencing at least one inappropriate shock during 1 to 5 years of follow-up. The limitation of the evidence reviewed in this study is low quality evidence for adverse events post-hospitalization. Evidence is predominantly from mixed primary and secondary prevention populations. In-hospital adverse events after ICD implantation are infrequent. The estimates for long-term adverse events are uncertain. Up to one-fifth of patients receive inappropriate shocks.

PA32540 (a coordinated-delivery tablet of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: Results of two 6-month, phase 3 studies

Discontinuations and/or interruptions in aspirin therapy for secondary cardioprotection due to upper gastrointestinal (UGI) complications or symptoms have been shown to increase the risk for subsequent cardiovascular events. PA32540 is a coordinated-delivery, combination tablet consisting of enteric-coated aspirin (EC-ASA) 325 mg and immediate-release (IR) omeprazole 40 mg. Two identically-designed, 6-month, randomized, double-blind trials evaluated PA32540 vs. EC-ASA 325 mg in a secondary cardiovascular disease prevention population taking aspirin 325 mg daily for ≥3 months and at risk for ASA-associated gastric ulcers (GUs). The combined study population was 1049 subjects (524 randomized to PA32540, 525 to EC-ASA 325 mg). The primary endpoint was the occurrence of endoscopically-determined gastric ulceration over 6 months. Safety outcomes included the rates of major adverse cardiovascular events (MACE) and UGI symptoms. Significantly fewer PA32540-treated subjects (3.2%) developed endoscopic GUs vs. EC-ASA 325 mg-treated subjects (8.6%) (P < .001). Overall occurrence of MACE was low (2.1%), with no significant differences between treatments in types or incidence of MACE. PA32540-treated subjects had significantly fewer UGI symptoms (P < .001) and significantly fewer discontinuations due to pre-specified UGI adverse events (1.5% vs. 8.2%, respectively; P < .001). PA32540 reduced the incidence of endoscopic GUs compared to EC-ASA 325 mg, but with a similar cardiovascular event profile. Due to fewer UGI symptoms, continuation on aspirin therapy was greater in the PA32540 treatment arm.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Dyslipidemia, Coronary Artery Calcium, and Incident Atherosclerotic Cardiovascular Disease

Background— Worldwide clinical practice guidelines for dyslipidemia emphasize allocating statin therapy to those at the highest absolute atherosclerotic cardiovascular disease (CVD) risk. Methods and Results— We examined 5534 Multi-Ethnic Study of Atherosclerosis (MESA) participants who were not on baseline medications for dyslipidemia. Participants were classified by baseline coronary artery calcium (CAC) score (&gt;0, ≥100) and the common clinical scheme of counting lipid abnormalities (LA), including low-density lipoprotein cholesterol ≥3.36 mmol/L (130 mg/dL), high-density lipoprotein cholesterol &lt;1.03 mmol/L (40 mg/dL) for men or &lt;1.29 mmol/L (50 mg/dL) for women, and triglycerides ≥1.69 mmol/L (150 mg/dL). Our main outcome measure was incident CVD (myocardial infarction, angina resulting in revascularization, resuscitated cardiac arrest, stroke, cardiovascular death). Over a median follow-up of 7.6 years, more than half of events (55%) occurred in the 21% of participants with CAC ≥100. Conversely, 65% of events occurred in participants with 0 or 1 LA. In those with CAC ≥100, CVD rates ranged from 22.7 to 29.5 per 1000 person-years across LA categories. In contrast, with CAC=0, CVD rates ranged from 2.7 to 5.9 per 1000 person-years across LA categories. Individuals with 0 LA and CAC ≥100 had a higher event rate compared with individuals with 3 LA but CAC=0 (22.7 versus 5.9 per 1000 person-years). Similar results were obtained when we classified LA using data set quartiles of total cholesterol/high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol, or low-density lipoprotein particle concentration and guideline categories of low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol. Conclusions— CAC may have the potential to help match statin therapy to absolute CVD risk. Across the spectrum of dyslipidemia, event rates similar to secondary prevention populations were observed for patients with CAC ≥100.

Impact of Implantable Cardioverter-Defibrillator Therapy on a Secondary Prevention Population—Reply

Impact of Implantable Cardioverter-Defibrillator Therapy on a Secondary Prevention Population—Reply

Low-Dose Aspirin and Upper Gastrointestinal Bleeding in Primary Versus Secondary Cardiovascular Prevention

The benefit-risk profile of low-dose aspirin in primary prevention of cardiovascular disease is unclear. We sought to quantify upper gastrointestinal bleeding (UGIB) risk associated with low-dose aspirin in secondary versus primary prevention patients. We performed a population-based nested case-control study using The Health Improvement Network (THIN) Database between 2000 and 2007. We identified 2049 cases of UGIB and 20,000 controls, frequency-matched to the cases on age, sex, and calendar year, who were subdivided into primary (without previous cardiovascular disease) and secondary (with previous cardiovascular disease) prevention populations. We estimated the relative risk of UGIB associated with the use of low-dose aspirin by multivariate logistic regression. The UGIB risk in patients taking low-dose aspirin relative to nonusers was significantly higher in the primary (adjusted relative risk, 1.90; 95% confidence interval, 1.59-2.26) than in the secondary (relative risk, 1.40; 95% confidence interval, 1.14-1.72; P value for the difference=0.0014) prevention cohort. However, as the baseline risk of UGIB was lower in the primary than in the secondary prevention cohort, numbers needed to harm per 1 year of low-dose aspirin use were 601 and 391 for primary and secondary prevention, respectively. The relative risk of UGIB in patients taking low-dose aspirin is higher when used for primary than for secondary cardiovascular disease prevention, but this difference is more than compensated by the lower baseline risk in the primary prevention population. Such estimates are important for an assessment of the net clinical benefit in primary prevention.

Lipoprotein(a) for Risk Assessment in Patients With Established Coronary Artery Disease

The purpose of this study was to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p= 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was≥130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p< 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol<130 mg/dl (OR:1.20, 95% CI: 0.90 to 1.60, p= 0.21). Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear.

PCV96 - Cost-Effectiveness of Increasing Statin Adherence for Primary and Secondary Prevention in Community Pharmacies

Objectives: Therapy persistence is important to achieve optimal clinical benefits of statin therapy. The aim of this study was to determine the cost-effectiveness of pharmaceutical care in community pharmacies, aimed to increase persistence with statin therapy for both primary and secondary prevention of cardiovascular events (CVEs). Methods: The effectiveness of the Dutch pharmaceutical care program MeMO on improving statin therapy persistence was measured in 500 patients and compared to 502 control patients. Time-investments of the program were also collected. Markov models with lifelong time-horizons were developed to estimate the influence of the program on CVEs: Stroke, myocardial infarction (MI), revascularization and mortality. The efficacy of statins, taken from large clinical trials in primary and secondary prevention, were adjusted for therapy persistence. A Dutch health care provider's perspective was adopted for the analysis and probabilistic sensitivity analyses were performed. Results: Patients in the MeMO program had a lower risk for non-persistence, RR = 0.50 (0.40-0.63), the effect was similar in primary and secondary prevention. In a cohort of 1,000 patients, 60% of whom had a history of CVE, the MeMO program resulted in a reduction of 8 non-fatal strokes 2 fatal strokes, 16 non-fatal MIs, 7 fatal MIs and 14 revascularizations. Additional medication, disease management and intervention costs in the MeMO program were € 375,000; the cost-savings due to reduced CVEs were € 450,000. Thus, the MeMO program resulted in 83 quality-adjusted life-years (QALYs) gained and cost-savings of € 75,000. Clinical benefits and cost-savings were highest in the secondary prevention population. Conclusions: Pharmaceutical care in community pharmacies can improve statin therapy persistence, resulting in more optimal prevention of CVEs. The MeMO program resulted in considerable clinical benefits and overall cost-savings. Persistence and adherence improving programs in community pharmacies may provide good value for money and health care insurers should consider reimbursing these activities in The Netherlands.

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