Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease

BACKGROUND

Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown.

METHODS

Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts — 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women’s Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) — and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet.

RESULTS

The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category.

CONCLUSIONS

Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.)

Reference: N Engl J Med 2016; 375:2349-2358December 15, 2016

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial

Importance  Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated.

Objective  To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients.

Design, Setting, and Participants  The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography.

Interventions  Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins.

Main Outcomes and Measures  The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated.

Results  Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, −56.5 mg/dL [95% CI, −59.7 to −53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, −1.0% [95% CI, −1.8% to −0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, −4.9 mm3 [95% CI, −7.3 to −2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV).

Conclusions and Relevance  Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT01813422

Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies

Objectives To investigate the association between long term intake of individual saturated fatty acids (SFAs) and the risk of coronary heart disease, in two large cohort studies.

Design Prospective, longitudinal cohort study.

Setting Health professionals in the United States.

Participants 73 147 women in the Nurses’ Health Study (1984-2012) and 42 635 men in the Health Professionals Follow-up Study (1986-2010), who were free of major chronic diseases at baseline.

Main outcome measure Incidence of coronary heart disease (n=7035) was self-reported, and related deaths were identified by searching National Death Index or through report of next of kin or postal authority. Cases were confirmed by medical records review.

Results Mean intake of SFAs accounted for 9.0-11.3% energy intake over time, and was mainly composed of lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), and stearic acid (18:0; 8.8-10.7% energy). Intake of 12:0, 14:0, 16:0 and 18:0 were highly correlated, with Spearman correlation coefficients between 0.38 and 0.93 (all P<0.001). Comparing the highest to the lowest groups of individual SFA intakes, hazard ratios of coronary heart disease were 1.07 (95% confidence interval 0.99 to 1.15; Ptrend=0.05) for 12:0, 1.13 (1.05 to 1.22; Ptrend<0.001) for 14:0, 1.18 (1.09 to 1.27; Ptrend<0.001) for 16:0, 1.18 (1.09 to 1.28; Ptrend<0.001) for 18:0, and 1.18 (1.09 to 1.28; Ptrend<0.001) for all four SFAs combined (12:0-18:0), after multivariate adjustment of lifestyle factors and total energy intake. Hazard ratios of coronary heart disease for isocaloric replacement of 1% energy from 12:0-18:0 were 0.92 (95% confidence interval 0.89 to 0.96; P<0.001) for polyunsaturated fat, 0.95 (0.90 to 1.01; P=0.08) for monounsaturated fat, 0.94 (0.91 to 0.97; P<0.001) for whole grain carbohydrates, and 0.93 (0.89 to 0.97; P=0.001) for plant proteins. For individual SFAs, the lowest risk of coronary heart disease was observed when the most abundant SFA, 16:0, was replaced. Hazard ratios of coronary heart disease for replacing 1% energy from 16:0 were 0.88 (95% confidence interval 0.81 to 0.96; P=0.002) for polyunsaturated fat, 0.92 (0.83 to 1.02; P=0.10) for monounsaturated fat, 0.90 (0.83 to 0.97; P=0.01) for whole grain carbohydrates, and 0.89 (0.82 to 0.97; P=0.01) for plant proteins.

Conclusions Higher dietary intakes of major SFAs are associated with an increased risk of coronary heart disease. Owing to similar associations and high correlations among individual SFAs, dietary recommendations for the prevention of coronary heart disease should continue to focus on replacing total saturated fat with more healthy sources of energy.

Reference: BMJ 2016;355:i5796

Prolonged dual antiplatelet therapy in stable coronary disease: comparative observational study of benefits and harms in unselected versus trial populations

Objective To estimate the potential magnitude in unselected patients of the benefits and harms of prolonged dual antiplatelet therapy after acute myocardial infarction seen in selected patients with high risk characteristics in trials.

Design Observational population based cohort study.

Setting PEGASUS-TIMI-54 trial population and CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records).

Participants 7238 patients who survived a year or more after acute myocardial infarction.

Interventions Prolonged dual antiplatelet therapy after acute myocardial infarction.

Main outcome measures Recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease. Fatal, severe, or intracranial bleeding.

Results 1676/7238 (23.1%) patients met trial inclusion and exclusion criteria (“target” population). Compared with the placebo arm in the trial population, in the target population the median age was 12 years higher, there were more women (48.6% v 24.3%), and there was a substantially higher cumulative three year risk of both the primary (benefit) trial endpoint of recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease (18.8% (95% confidence interval 16.3% to 21.8%) v 9.04%) and the primary (harm) endpoint of fatal, severe, or intracranial bleeding (3.0% (2.0% to 4.4%) v 1.26% (TIMI major bleeding)). Application of intention to treat relative risks from the trial (ticagrelor 60 mg daily arm) to CALIBER’s target population showed an estimated 101 (95% confidence interval 87 to 117) ischaemic events prevented per 10 000 treated per year and an estimated 75 (50 to 110) excess fatal, severe, or intracranial bleeds caused per 10 000 patients treated per year. Generalisation from CALIBER’s target subgroup to all 7238 real world patients who were stable at least one year after acute myocardial infarction showed similar three year risks of ischaemic events (17.2%, 16.0% to 18.5%), with an estimated 92 (86 to 99) events prevented per 10 000 patients treated per year, and similar three year risks of bleeding events (2.3%, 1.8% to 2.9%), with an estimated 58 (45 to 73) events caused per 10 000 patients treated per year.

Conclusions This novel use of primary-secondary care linked electronic health records allows characterisation of “healthy trial participant” effects and confirms the potential absolute benefits and harms of dual antiplatelet therapy in representative patients a year or more after acute myocardial infarction.

BMJ 2016;353:i3163

Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients With Stable Coronary Heart Disease

Importance  Precise stratification of cardiovascular risk in patients with coronary heart disease (CHD) is needed to inform treatment decisions.

Objective  To derive and validate a score to predict risk of cardiovascular outcomes among patients with CHD, using large-scale analysis of circulating proteins.

Design, Setting, and Participants  Prospective cohort study of participants with stable CHD. For the derivation cohort (Heart and Soul study), outpatients from San Francisco were enrolled from 2000 through 2002 and followed up through November 2011 (≤11.1 years). For the validation cohort (HUNT3, a Norwegian population-based study), participants were enrolled from 2006 through 2008 and followed up through April 2012 (5.6 years).

Exposures  Using modified aptamers, 1130 proteins were measured in plasma samples.

Main Outcomes and Measures  A 9-protein risk score was derived and validated for 4-year probability of myocardial infarction, stroke, heart failure, and all-cause death. Tests, including the C statistic, were used to assess performance of the 9-protein risk score, which was compared with the Framingham secondary event model, refit to the cohorts in this study. Within-person change in the 9-protein risk score was evaluated in the Heart and Soul study from paired samples collected 4.8 years apart.

Results  From the derivation cohort, 938 samples were analyzed, participants’ median age at enrollment was 67.0 years, and 82% were men. From the validation cohort, 971 samples were analyzed, participants’ median age at enrollment was 70.2 years, and 72% were men. In the derivation cohort, C statistics were 0.66 for refit Framingham, 0.74 for 9-protein, and 0.75 for refit Framingham plus 9-protein models. In the validation cohort, C statistics were 0.64 for refit Framingham, 0.70 for 9-protein, and 0.71 for refit Framingham plus 9-protein models. Adding the 9-protein risk score to the refit Framingham model increased the C statistic by 0.09 (95% CI, 0.06-0.12) in the derivation cohort, and in the validation cohort, the C statistic was increased by 0.05 (95% CI, 0.02-0.09). Compared with the refit Framingham model, the integrated discrimination index for the 9-protein model was 0.12 (95% CI, 0.08-0.16) in the derivation cohort and 0.08 (95% CI, 0.05-0.10) in the validation cohort. In analysis of paired samples among 139 participants with cardiovascular events after the second sample, absolute within-person annualized risk increased more for the 9-protein model (median, 1.86% [95% CI, 1.15%-2.54%]) than for the refit Framingham model (median, 1.00% [95% CI, 0.87%-1.19%]) (P = .002), while among 375 participants without cardiovascular events, both scores changed less and similarly (P = .30).

Conclusions and Relevance  Among patients with stable CHD, a risk score based on 9 proteins performed better than the refit Framingham secondary event risk score in predicting cardiovascular events, but still provided only modest discriminative accuracy. Further research is needed to assess whether the score is more accurate in a lower-risk population.

JAMA. 2016;315(23):2532-2541

Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention

Importance  Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding.

Objective  To develop a clinical decision tool to identify patients expected to derive benefit vs harm from continuing thienopyridine beyond 1 year after PCI.

Design, Setting, and Participants  Among 11 648 randomized DAPT Study patients from 11 countries (August 2009-May 2014), a prediction rule was derived stratifying patients into groups to distinguish ischemic and bleeding risk 12 to 30 months after PCI. Validation was internal via bootstrap resampling and external among 8136 patients from 36 countries randomized in the PROTECT trial (June 2007-July 2014).

Exposures  Twelve months of open-label thienopyridine plus aspirin, then randomized to 18 months of continued thienopyridine plus aspirin vs placebo plus aspirin.

Main Outcomes and Measures  Ischemia (myocardial infarction or stent thrombosis) and bleeding (moderate or severe) 12 to 30 months after PCI.

Results  Among DAPT Study patients (derivation cohort; mean age, 61.3 years; women, 25.1%), ischemia occurred in 348 patients (3.0%) and bleeding in 215 (1.8%). Derivation cohort models predicting ischemia and bleeding had c statistics of 0.70 and 0.68, respectively. The prediction rule assigned 1 point each for myocardial infarction at presentation, prior myocardial infarction or PCI, diabetes, stent diameter less than 3 mm, smoking, and paclitaxel-eluting stent; 2 points each for history of congestive heart failure/low ejection fraction and vein graft intervention; −1 point for age 65 to younger than 75 years; and −2 points for age 75 years or older. Among the high score group (score ≥2, n = 5917), continued thienopyridine vs placebo was associated with reduced ischemic events (2.7% vs 5.7%; risk difference [RD], −3.0% [95% CI, −4.1% to −2.0%], P < .001) compared with the low score group (score <2, n = 5731; 1.7% vs 2.3%; RD, −0.7% [95% CI, −1.4% to 0.09%], P = .07; interaction P < .001). Conversely, continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% vs 1.4%; RD, 0.4% [95% CI, −0.3% to 1.0%], P = .26) compared with the low score group (3.0% vs 1.4%; RD, 1.5% [95% CI, 0.8% to 2.3%], P < .001; interaction P = .02). Among PROTECT patients (validation cohort; mean age, 62 years; women, 23.7%), ischemia occurred in 79 patients (1.0%) and bleeding in 37 (0.5%), with a c statistic of 0.64 for ischemia and 0.64 for bleeding. In this cohort, the high-score patients (n = 2848) had increased ischemic events compared with the low-score patients and no significant difference in bleeding.

Conclusion and Relevance  Among patients not sustaining major bleeding or ischemic events 1 year after PCI, a prediction rule assessing late ischemic and bleeding risks to inform dual antiplatelet therapy duration showed modest accuracy in derivation and validation cohorts. This rule requires further prospective evaluation to assess potential effects on patient care, as well as validation in other cohorts.

JAMA. 2016;315(16):1735-1749. doi:10.1001/jama.2016.3775.

Association Between Rotating Night Shift Work and Risk of Coronary Heart Disease Among Women

Importance  Prospective studies linking shift work to coronary heart disease (CHD) have been inconsistent and limited by short follow-up.

Objective  To determine whether rotating night shift work is associated with CHD risk.

Design, Setting, and Participants  Prospective cohort study of 189 158 initially healthy women followed up over 24 years in the Nurses’ Health Studies (NHS [1988-2012]: N = 73 623 and NHS2 [1989-2013]: N = 115 535).

Exposures  Lifetime history of rotating night shift work (≥3 night shifts per month in addition to day and evening shifts) at baseline (updated every 2 to 4 years in the NHS2).

Main Outcomes and Measures  Incident CHD; ie, nonfatal myocardial infarction, CHD death, angiogram-confirmed angina pectoris, coronary artery bypass graft surgery, stents, and angioplasty.

Results  During follow-up, 7303 incident CHD cases occurred in the NHS (mean age at baseline, 54.5 years) and 3519 cases in the NHS2 (mean age, 34.8 years). In multivariable-adjusted Cox proportional hazards models, increasing years of baseline rotating night shift work were associated with a significantly higher CHD risk in both cohorts. In the NHS, the age-standardized incidence rate (IR) for less than 5 years of rotating night shift work per 100 000 person-years was 435.1 (hazard ratio [HR], 1.02; 95% CI, 0.97-1.08); the IR for 5 to 9 years of rotating night shift work was 525.7 (HR, 1.12; 95% CI, 1.02-1.22); and the IR for 10 years or more of rotating night shift work was 596.9 (HR, 1.18; 95% CI, 1.10-1.26; P<.001 for trend) vs an IR of 425.5 in women who never worked rotating night shifts. In the NHS2, the IR for less than 5 years was 130.6 (HR, 1.05; 95% CI, 0.97-1.13); the IR for 5 to 9 years was 151.6 (HR,1.12; 95% CI, 0.99-1.26); and the IR for 10 years or more was 178.0 (HR, 1.15; 95% CI, 1.01-1.32; P = .01 for trend) vs an IR of 122.6 in women who never worked rotating night shifts. In the NHS, the association between duration of rotating night shift work and CHD was stronger in the first half of follow-up (IR for <5 years, 382.4; HR, 1.10 [95% CI, 1.01-1.21]; IR for 5-9 years, 483.1; HR, 1.19 [95% CI, 1.03-1.39]; and IR for ≥10 years, 494.4; HR, 1.27 [95% CI, 1.13-1.42]; P<.001 for trend) than in the second half (IR for <5 years, 424.8; HR, 0.98 [95% CI, 0.92-1.05]; IR for 5-9 years, 520.7; HR, 1.08 [95% CI, 0.96-1.21]; IR for ≥10 years, 556.2; HR, 1.13 [95% CI, 1.04-1.24]; P = .004 for trend; P = .02 for interaction), suggestive of waning risk after cessation of shift work. Longer time since quitting shift work was associated with decreased CHD risk among ever shift workers in the NHS2 (P<.001 for trend).

Conclusions and Relevance  Among women who worked as registered nurses, longer duration of rotating night shift work was associated with a statistically significant but small absolute increase in CHD risk. Further research is needed to explore whether the association is related to specific work hours and individual characteristics.

JAMA. 2016;315(16):1726-1734. doi:10.1001/jama.2016.4454.