Abstract
BACKGROUND
Risk factor control is the cornerstone of managing stable ischemic heart disease but is often not achieved. Predictors of risk factor control in a randomized clinical trial have not been described.
METHODS AND RESULTS
The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) randomized individuals with at least moderate inducible ischemia and obstructive coronary artery disease to an initial invasive or conservative strategy in addition to optimal medical therapy. The primary aim of this analysis was to determine predictors of meeting trial goals for LDL-C (low-density lipoprotein cholesterol, goal <70 mg/dL) or systolic blood pressure (SBP, goal <140 mm Hg) at 1 year post-randomization. We included all randomized participants in the ISCHEMIA trial with baseline and 1-year LDL-C and SBP values by January 28, 2019. Among the 3984 ISCHEMIA participants (78% of 5179 randomized) with available data, 35% were at goal for LDL-C, and 65% were at goal for SBP at baseline. At 1 year, the percent at goal increased to 52% for LDL-C and 75% for SBP. Adjusted odds of 1-year LDL-C goal attainment were greater with older age (odds ratio [OR], 1.11 [95% CI, 1.03–1.20] per 10 years), lower baseline LDL-C (OR, 1.19 [95% CI, 1.17–1.22] per 10 mg/dL), high-intensity statin use (OR, 1.30 [95% CI, 1.12–1.51]), nonwhite race (OR, 1.32 [95% CI, 1.07–1.63]), and North American enrollment compared with other regions (OR, 1.32 [95% CI, 1.06–1.66]). Women were less likely than men to achieve 1-year LDL-C goal (OR, 0.68 [95% CI, 0.58–0.80]). Adjusted odds of 1-year SBP goal attainment were greater with lower baseline SBP (OR, 1.27 [95% CI, 1.22–1.33] per 10 mm Hg) and with North American enrollment (OR, 1.35 [95% CI, 1.04–1.76]).
CONCLUSIONS
In ISCHEMIA, older age, male sex, high-intensity statin use, lower baseline LDL-C, and North American location predicted 1-year LDL-C goal attainment, whereas lower baseline SBP and North American location predicted 1-year SBP goal attainment. Future studies should examine the effects of sex disparities, international practice patterns, and provider behavior on risk factor control.
Keywords: blood pressure, cardiovascular disease, goals, heart disease, risk factor
There is robust epidemiologic1 and clinical trial evidence2–5 that atherosclerotic cardiovascular disease risk factor control reduces atherosclerotic cardiovascular disease events and improves survival. Nevertheless, risk factor control has proved difficult to achieve for patients with stable ischemic heart disease (SIHD) in clinical practice,2,6 community-based populations,3 and in major randomized clinical trials,4,5,7 suggesting that innovative strategies are needed to improve risk factor goal attainment.8 Participants in randomized trials of SIHD typically receive repeated standardized assessments of cardiac risk factors, health behaviors, medication adherence, and quality of life. Such serial surveillance could be used to identify predictors of risk factor control and to identify a cohort to target for more intensive or different approaches to atherosclerotic cardiovascular disease risk factor control.
Optimal medical therapy (OMT) refers to evidence-based, comprehensive secondary prevention with pharmacological and lifestyle interventions. Prior studies have described individuals in randomized trials of SIHD that attain OMT goals,5,7–9 and improved atherosclerotic cardiovascular disease outcomes with increasing risk factor control.4,7,9 Observational registries6,10 and retrospective cohort studies have also described racial/ethnic gaps and sex disparities in the use of, and adherence to, evidence-based therapies after a myocardial infarction 11 or in the setting of uncontrolled hypertension.12 To date, predictors of OMT goal attainment have not been systematically reported in a large, international, randomized strategy trial for high-risk patients with SIHD and could provide context for future studies. Reduction in low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) are primary targets of risk factor management for SIHD patients in clinical practice and randomized trials. Therefore, we analyzed interim data from ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) to describe characteristics of participants, sites, and regions at randomization associated LDL-C and SBP goal attainment after 1 year of participation in the trial.
METHODS
Deidentified participant data and data dictionary will be available starting June 30, 2022. Methods of data sharing to be determined based on National Institute of Health data sharing policy and in discussion with National Institute of Health and National Heart, Lung and Blood Institute trial officer. Each enrolling site obtained approval from its local or national institutional review board or ethics committee. Every participant was required to provide written consent before enrollment and randomization.13 Details of the study design have been previously published.13,14 In brief, the primary aim of ISCHEMIA is to assess whether an initial invasive strategy compared with a conservative strategy, on a background of OMT, will reduce the composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest. The first enrollment was on July 26, 2012; the last randomization was on January 31, 2018.13,14 ISCHEMIA trial participants with complete baseline and 1-year follow-up data finalized and entered as of January 28, 2019, were included for this analysis.
Multiple strategies were used to achieve the previously defined OMT goals in ISCHEMIA.13 These strategies were employed at the country, site, and participant level, and were performed regardless of treatment group assignment. Uniform algorithms for counseling were developed by the Clinical Coordinating Center and distributed to the sites.13 Approximately 30% of sites received or were reimbursed to provide guideline-directed medications at no cost to participants. Provision of medications by pharmaceutical companies depended on multiple factors, including approval of the drug in a given country, other regulatory issues that limited drug donation, and willingness of sites to accept and store medications. Similarly, sites in countries without universal health coverage did not uniformly accept the offer for reimbursement of medication prescriptions. Central monitoring of OMT goal attainment was performed by the Clinical Coordinating Center at the regional, country, and site levels throughout the trial. The full schedule of study assessments, including LDL-C and SBP, is available in the online supplement the ISCHEMIA trial rationale and design paper.13 In brief, required labs, including lipids (preferably fasting), were required at the randomization and 3 month visit, and least semiannually until accrual of 36 months follow-up. Similarly, vital signs, including blood pressure (BP), were required at visits at 1.5 and 3 months and thereafter at least semiannually until accrual of 36 months of follow-up.13 Assessment schedules and algorithms for attainment of OMT targets including LDL-C and SBP were identical at all sites. Multiple methods were used to assist sites and participants to attain LDL-C and SBP goals, as described in detail previously.13 Additionally, the ISCHEMIA Clinical Coordinating Center distributed memoranda to all sites summarizing current evidence for maximal LDL-C reduction, international consensus guidelines on BP assessment, the availability of reimbursement for purchase of automated BP monitors, and in March 2018 guidance on the use of home BP in lieu of in-clinic assessments, when appropriate for participants. All ISCHEMIA sites received a monthly report with participantlevel data on OMT goal attainment. Sites with multiple participants not meeting OMT goals were contacted regularly by 2 of the authors (Dr Newman and Dr Maron) to review prescription of lipid-lowering and antihypertensive medication. Monitoring and recommendations on LDL-C and SBP goal attainment were performed without knowledge of treatment group assignment.
Goals for SBP and Low-Density Lipoprotein Cholesterol
Similar to previous strategy trials for the management of patients with SIHD,8 we used the National Cholesterol Education Program optional LDL cholesterol goal of <70 mg/ dL for very high-risk patients.5,15 The SBP goal of <140 mm Hg was based on the prevailing guidelines at the time of trial launch.16 In response to a change in clinical practice guidelines for SBP management of patients with SIHD, this risk factor goal was changed to <130 mm Hg in April 2018.13,17 Because this change occurred after the majority of people in this analytic cohort had completed 1-year follow-up, the SBP goal of <140 mm Hg was used for this analysis.
Participant Characteristics
Baseline variables included for analyses of 1-year goal attainment are listed in Table I in the Data Supplement. Race was categorized as White, Black, Asian, and Other/Multiple. The latter includes American Indian or Alaskan Native, Native Hawaiian or other Pacific Islander, or multiple races reported. Hispanic or Latino includes people of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin. Medication adherence was defined using the Morisky Green Levine Medication Adherence Scale.18 A summary binary variable was created by coding those who responded strongly agree, agree, don’t know, or refuse to any of the 4 questions: (1) I sometimes forget to take my medicines, (2) I am sometimes careless about taking my medicines, (3) when I feel better I sometimes stop taking my medicines, and (4) if I feel worse when I take my medicine, sometimes I stop taking it, as nonadherent; otherwise, patients were coded as adherent.19 The short form of the Seattle Angina Questionnaire20 was used to characterize Seattle Angina Questionnaire domain scores at baseline and as a covariate for 1-year goal attainment. The EuroQoL is a self-administered 5-item health assessment and visual analog scale that was used to characterize participants’ health status.21 Because the goal of health status assessments was to describe the ISCHEMIA population of this analysis, only the visual analog scale without societal-based utility weights was used.
Statistical Analysis
Participant baseline characteristics were summarized overall and within subgroups defined by LDL-C and SBP goal attainment status at baseline using medians (first quartile, third quartile) for continuous variables and counts (percentages) for categorical variables. The proportion of individuals attaining LDL-C and SBP goals at 1 year was calculated across categories of baseline variables. Distributions of LDL-C for all participants at baseline and at 1 year were investigated using box and whisker plots, with outliers defined as 1.5×interquartile range above or below the highest or lowest quartile. The multivariable associations of 1-year LDL-C and SBP goal attainment with a prespecified set of baseline characteristics were assessed using logistic regression with separate models for predicting LDL-C and SBP. Parameters were estimated using generalized estimating equations methodology with an exchangeable working correlation structure and model-based SEs to account for clustering of individuals within enrolling trial sites. Odds ratios comparing the frequency of 1-year goal attainment across levels of baseline covariates were calculated and presented with 95% CIs. To simplify graphical and tabular presentations, interaction terms were not tested, and the effects of continuous covariates (age, body mass index, LDL-C, SBP) were approximated as linear. All analyses were performed using SAS 9.4 (Cary, NC).
RESULTS
Baseline Characteristics
Characteristics of participants overall and by categories of LDL-C and SBP goal status at baseline are shown in Table 1. Of the 5179 ISCHEMIA trial participants, there were 3984 (78%) who had complete LDL-C and SBP data at baseline and 1-year follow-up available for analysis as of January 28, 2019. Comparison of baseline characteristics of participants that were included and those excluded for incomplete data by the cutoff date used for this analysis is presented in Table II in the Data Supplement. The median age was 64 years, 23% were female, and 35% were of nonwhite race. The prevalence of diabetes mellitus and hypertension at baseline was 41% and 73%, respectively. Approximately 20% of patients had a prior myocardial infarction, 21% prior percutaneous coronary intervention, and 4% prior coronary artery bypass grafting. Almost all (95%) were on a statin, and high-intensity statin therapy at baseline was more common among individuals at LDL-C goal at baseline (42%) compared with those not at goal (34%). Greater than 80% were taking antihypertensive or antianginal medications at baseline. The number of medications overall and the number of antihypertensive medications were similar across groups of baseline LDL-C and SBP. Approximately 75% of individuals were adherent with medications. Medication provision or reimbursement was available for ≈30% of participants.
Table 1.
Baseline Demographics by Baseline LDL-C and SBP
| Baseline Characteristics | Overall (N=3984) | Baseline LDL-C, mg/dL | Baseline SBP, mm Hg | ||
|---|---|---|---|---|---|
| <70 (n=1379) | ≥70 (n=2605) | <140 (n=2584) | ≥140 (n=1400) | ||
| Age, y | |||||
| Median (Q1, Q3) | 64 (58, 70) | 65 (58, 71) | 63 (57, 69) | 63 (56, 69) | 65 (59, 71) |
| ≥ 75 | 479 (12.0%) | 200 (14.5%) | 279 (10.7%) | 280 (10.8%) | 199 (14.2%) |
| Sex, n (%) | |||||
| Male | 3087 (77.5) | 1128 (81.8) | 1959 (75.2) | 2021 (78.2) | 1066 (76.1) |
| Female | 897 (22.5) | 251 (18.2) | 646 (24.8) | 563 (21.8 | 334 (23.9) |
| Race, n (%) | |||||
| White | 2573 (65.0) | 847 (61.9) | 1726 (66.7) | 1629 (63.5) | 944 (67.8) |
| Black | 139 (3.5%) | 41 (3.0%) | 98 (3.8%) | 91 (3.5%) | 48 (3.4) |
| Asian | 1222 (30.9) | 471 (34.4) | 751 (29.0) | 827 (32.2) | 395 (28.4) |
| Other/multiple* | 24 (0.6) | 10 (0.7) | 14 (0.5) | 18 (0.7) | 6 (0.4) |
| Ethnicity, n (%) | |||||
| Hispanic or Latino† | 560 (15.2) | 156 (12.5) | 404 (16.6) | 341 (14.4) | 219 (16.6) |
| Non-Hispanic or Latino | 3132 (84.8) | 1095 (87.5) | 2037 (83.4) | 2035 (85.6) | 1097 (83.4) |
| Region, n (%) | |||||
| Africa/Middle East/Pacifica | 78 (2.0) | 31 (2.2) | 47 (1.8) | 45 (1.7) | 33 (2.4) |
| Asia | 1312 (32.9) | 436 (31.6) | 876 (33.6) | 903 (34.9) | 409 (29.2) |
| North America | 897 (22.5) | 402 (29.2) | 495 (19.0) | 619 (24.0) | 278 (19.9) |
| Europe | 1315 (33.0)) | 408 (29.6) | 907 (34.8) | 789 (30.5) | 526 (37.6) |
| Latin America‡ | 382 (9.6) | 102 (7.4) | 280 (10.7) | 228 (8.8) | 154 (11.0) |
| Diabetes mellitus, n (%) | 1633 (41.0) | 670 (48.6) | 963 (37.0) | 998 (38.6) | 635 (45.4) |
| Hypertension, n (%) | 2890 (72.8) | 996 (72.5) | 1894 (73.0) | 1756 (68.2) | 1134 (81.3) |
| BMI, kg/m3 | |||||
| Median (Q1, Q3) | 28 (25, 31) | 28 (25, 31) | 28 (25, 31) | 27 (25, 31) | 28 (25, 32) |
| Current smoking, n (%) | 480 (12.1) | 129 (9.4) | 351 (13.5) | 349 (13.5) | 131 (9.4) |
| Prior MI, n (%) | 784 (19.7) | 302 (22.0) | 482 (18.6) | 536 (20.8) | 248 (17.8) |
| Prior stroke, n (%) | 104 (2.6) | 35 (2.5) | 69 (2.6) | 67 (2.6) | 37 (2.6) |
| Prior PCI, n (%) | 832 (20.9) | 312 (22.7) | 520 (20.0) | 551 (21.3) | 281 (20.1) |
| Prior CABG, n (%) | 140 (3.5) | 52 (3.8) | 88 (3.4) | 95 (3.7) | 45 (3.2) |
| Lipid-lowering medications, n (%) | |||||
| Statin | 3785 (95.0) | 1363 (98.8) | 2422 (93.0) | 2464 (95.4) | 1321 (94.4) |
| High-intensity statin therapy§ | 1467 (36.8) | 579 (42.0) | 888 (34.1) | 987 (38.2) | 480 (34.3) |
| Ezetimibe | 160 (4.0) | 58 (4.2) | 102 (3.9) | 100 (3.9) | 60 (4.3) |
| Antihypertensive medications, n (%) | |||||
| β -blocker | 3226 (81.0) | 1142 (82.8) | 2084 (80.0) | 2125 (82.2) | 1101 (78.6) |
| ACE inhibitor /ARB | 2664 (66.9) | 937 (67.9) | 1727 (66.3) | 1661 (64.3) | 1003 (71.6) |
| CCB | 1220 (30.6) | 445 (32.3) | 775 (29.8) | 706 (27.3) | 514 (36.7) |
| Diuretic | 810 (20.3) | 265 (19.2) | 545 (20.9) | 452 (17.5) | 358 (25.6) |
| Total no. of medicines‖ | |||||
| Median (Q1, Q3) | 4 (4, 5) | 4 (4, 5) | 4 (3, 5) | 4 (3, 5) | 4 (4, 5) |
| Total no. of antihypertensive medications | |||||
| Median (Q1, Q3) | 2 (1, 3) | 2 (1, 3) | 2 (1, 3) | 2 (1, 3) | 2 (1, 3) |
| Baseline SAQ domain scores | |||||
| Physical limitation | |||||
| Median (Q1, Q3) | 92 (67, 100) | 92 (75, 100) | 92 (67, 100) | 92 (75, 100) | 92 (67, 100) |
| Angina frequency, n (%) | |||||
| Any angina in past month | 2586 (65.6) | 843 (61.6) | 1743 (67.8) | 1693 (66.2) | 893 (64.5) |
| No angina in past month (100) | 1354 (34.4) | 526 (38.4) | 828 (32.2) | 863 (33.8) | 491 (35.5) |
| Quality of life | |||||
| Median (Q1, Q3) | 63 (50, 88) | 63 (50, 88) | 63 (38, 75) | 63 (50, 88) | 63 (50, 75) |
| Summary score | |||||
| Median (Q1, Q3) | 77 (63, 88) | 79 (65, 89) | 76 (63, 88) | 77 (64, 88) | 77 (63, 88) |
| Very poor to good (0–74), n (%) | 1747 (44.3) | 550 (40.1) | 1197 (46.5) | 1129 (44.1) | 618 (44.6) |
| Good to excellent (75–100), n (%) | 2196 (55.7) | 821 (59.9) | 1375 (53.5) | 1429 (55.9) | 767 (55.4) |
| EuroQoL-5 dimension Health State Score | |||||
| Median (Q1, Q3) | 70 (60, 80) | 70 (60, 80) | 70 (60, 80) | 70 (60, 80) | 70 (60, 80) |
| Morisky Green Levine Adherence, n (%) | |||||
| Adherent | 2860 (74.7) | 1055 (79.1) | 1805 (72.3) | 1830 (73.8) | 1030 (76.2) |
| Nonadherent | 970 (25.3) | 279 (20.9) | 691 (27.7) | 648 (26.2) | 322 (23.8) |
| Medication donation/reimbursement, n (%) | 807 (20.3) | 316 (22.9) | 491 (18.8) | 521 (20.2) | 286 (20.4) |
ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BMI, body mass index; CABG, coronary artery bypass graft; CCB, calcium channel blocker; EQ-5D, EuroQoL; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; Q1, first quartile; Q3, third quartile; SAQ, Seattle Angina Questionnaire; and SBP, systolic blood pressure.
Other/multiple includes American Indian or Alaskan Native, Native Hawaiian or other Pacific Islander, or multiple races reported.
Includes people of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin.
Latin America includes South America countries and Mexico.
High-intensity dose of rosuvastatin or atorvastatin.
∥Include lipid-lowering, antihypertensive, and antiplatelet (aspirin±thienopyridine).
Participants at Goal at Baseline
At baseline, 1379 (35%) and 2584 (65%) were at goal for LDL-C or SBP, respectively. Men were more likely to be at goal for LDL-C (37%) and SBP (65%) at baseline than women (28% and 63%, respectively). Non-Hispanic white individuals were more likely to be at baseline goal for LDL-C (35%) and SBP (65%) than Hispanic or Latino individuals (28% and 61%, respectively). Regional differences in goal attainment were also present. The proportion at LDL-C goal at baseline ranged from 45% in North America to 27% in Latin America. In contrast, the proportion at SBP goal at baseline ranged from 69% in North America and Asia to 60% in Europe and Latin America.
Participants at Goal at 1 Year
From baseline to 1 year, among all participants (including those at goal and not at goal at baseline), the percent of individuals at goal for LDL-C or SBP increased from 35% to 52% and from 65% to 75%, respectively. Among those not at goal at baseline, 40% and 62% attained goals at 1 year for LDL-C and SBP, respectively. Figures 1 and 2 present the LDL-C and SBP values at baseline and 1 year overall and values for people who attained versus those who did not attain LDL-C and SBP goals at 1 year. A greater proportion of men than women achieved
Figure 1. LDL-C (low-density lipoprotein cholesterol) values at baseline and 1 y overall and by attainment of LDL-C goal.
Figure 2.
Systolic blood pressure (SBP) values at baseline and 1 y overall and by attainment of SBP goal.
1-year goals for LDL-C and SBP (Table 2). The percent attaining 1-year LDL-C goal was 58% versus 51% for participants treated versus not treated with high-intensity statin therapy at baseline. The proportion of people attaining LDL-C or SBP goal at 1 year was similar for those taking ≥2 versus <2 lipid-lowering or antihypertensive medications baseline (Table 2). Differences in baseline medical history and prior revascularization were observed for those attaining 1-year LDL-C or SBP goals, but the pattern was inconsistent. The proportion with 1-year LDL-C goal attainment was greater among individuals reporting adherence by the Morisky Green Levine Adherence Score and for sites with donated or reimbursed medications (Table 2). In contrast, the proportion of 1-year SBP goal attainment was similar for participants reporting adherence versus nonadherence, and for sites with compared to those without donated or reimbursed medications. Finally, there was no clear pattern between baseline anginal symptoms and 1-year LDL-C or SBP goal attainment.
Table 2.
Goal Attainment at 1 Year
| Baseline Characteristics | Attained LDL-C Goal (N=3984) | Attained SBP Goal (N=3984) |
|---|---|---|
| Overall | 2066/3984 (51.9) | 2977/3984 (74.7) |
| Age, y | ||
| <65 | 1029/2085 (49.4) | 1623/2085 (77.8) |
| ≥ 65 | 1037/1899 (54.6) | 1354/1899 (71.3) |
| Sex, n (%) | ||
| Male | 1690/3087 (54.7) | 2343/3087 (75.9) |
| Female | 376/897 (41.9) | 634/897 (70.7) |
| Race, n (%) | ||
| Nonwhite | 788/1385 (56.9) | 1058/1385 (76.4) |
| White | 1266/2573 (49.2) | 1899/2573 (73.8) |
| Diabetes mellitus, n (%) | ||
| Yes | 909/1633 (55.7) | 1169/1633 (71.6) |
| No | 1157/2351 (49.2) | 1808/2351 (76.9) |
| BMI, kg/m2, n (%) | ||
| <30 | 1407/2693 (52.2) | 2035/2693 (75.6) |
| ≥ 30 | 642/1267 (50.7) | 927/1267 (73.2) |
| Current smoking, n (%) | ||
| Yes | 219/480 (45.6) | 354/480 (73.8) |
| No | 1842/3499 (52.6) | 2618/3499 (74.8) |
| High-intensity statin therapy,* n (%) | ||
| Yes | 843/1467 (57.5) | 1114/1467 (75.9) |
| No | 792/1542 (51.4) | 1171/1542 (75.9) |
| ≥2 Lipid-lowering medications,† n (%) | ||
| Yes | 182/355 (51.3) | 273/355 (76.9) |
| No | 1884/3629 (51.9) | 2704/3629 (74.5) |
| ≥2 Antihypertensive medications,† n (%) | ||
| Yes | 1439/2778 (51.8) | 2030/2778 (73.1) |
| No | 627/1206 (52.0) | 947/1206 (78.5) |
| Hypertension, n (%) | ||
| Yes | 1471/2890 (50.9) | 2087/2890 (72.2) |
| No | 588/1079 (54.5) | 878/1079 (81.4) |
| Prior MI, n (%) | ||
| Yes | 381/784 (48.6) | 615/784 (78.4) |
| No | 1677/3188 (52.6) | 2353/3188 (73.8) |
| Prior stroke, n (%) | ||
| Yes | 49/104 (47.1) | 73/104 (70.2) |
| No | 2017/3880 (52.0) | 2904/3880 (74.8) |
| Prior PCI, n (%) | ||
| Yes | 402/832 (48.3) | 645/832 (77.5) |
| No | 1662/3150 (52.8) | 2330/3150 (74.0) |
| Prior CABG, n (%) | ||
| Yes | 70/140 (50.0) | 113/140 (80.7) |
| No | 1996/3844 (51.9) | 2864/3844 (74.5) |
| SAQ angina frequency, n (%) | ||
| Any angina in past month (0–99) | 1300/2586 (50.3) | 1959/2586 (75.8) |
| No angina in past month (100) | 746/1354 (55.1) | 985/1354 (72.7) |
| SAQ summary score, n (%) | ||
| Poor to good (0–74) | 913/1836 (49.7) | 1402/1836 (76.4) |
| Good to excellent (75–100) | 1136/2108 (53.9) | 1546/2108 (73.3) |
| Morisky Green Levine Adherence Score, n (%) | ||
| Adherent | 1527/2860 (53.4) | 2135/2860 (74.7) |
| Nonadherent | 467/970 (48.1) | 731/970 (75.4) |
| Region, n (%) | ||
| Africa/Middle East/Pacifica | 36/78 (46.2) | 57/78 (73.1) |
| Asia | 709/1312 (54.0) | 1043/1312 (79.5) |
| North America | 539/897 (60.1) | 705/897 (78.6) |
| Europe | 632/1315 (48.1) | 939/1315 (71.4) |
| Latin America | 150/382 (39.3) | 233/382 (61.0) |
| Medication donation/reimbursement, n (%) | ||
| Yes | 459/807 (56.9) | 607/807 (75.2) |
| No | 1607/3177 (50.6) | 2370/3177 (74.6) |
BMI indicates body mass index; CABG, coronary artery bypass graft; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; SAQ, Seattle Angina Questionnaire; and SBP, systolic blood pressure.
High-intensity dose of rosuvastatin or atorvastatin.
Medications listed under the categories of lipid-lowering and antihypertensive medications from Table 1.
Predictors of Goal Attainment at 1 Year
Figure 3 presents multivariable-adjusted odds ratios for the association between baseline characteristics and attainment of LDL-C or SBP goal at 1 year. Participants who were older, of nonwhite race, enrolled at North American sites, had lower baseline LDL-C and greater high-intensity statin use had increased adjusted odds of attaining the LDL-C goal by 1 year (Figure 3). Conversely, women and individuals with a prior percutaneous coronary intervention had lower odds of attaining the LDL-C goal by 1 year (Figure 3). For SBP, participants with a lower baseline SBP or LDL-C and participants from North American sites had increased adjusted odds of reaching SBP goal at 1 year. In contrast, individuals with older baseline age, diabetes mellitus, higher body mass index, current cigarette smoking, and those prescribed ≥2 antihypertensive medications had lower adjusted odds of reaching goal for SBP at 1 year (Figure 3). Results for LDL-C and SBP goal attainment were similar overall when the analysis cohort was restricted to participants not at goal at baseline for either LDL-C or SBP (Figure in the Data Supplement).
Figure 3. Multivariable odds ratios of goal attainment at 1 y (95% CI).
BMI indicates body mass index; CABG, coronary artery bypass grafting; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; SAQ, Seattle Angina Questionnaire; and SBP, systolic blood pressure. aHigh intensity dose of rosuvastatin or atorvastatin; blipid-lowering and antihypertensive medications as reported in Table 1.*P<0.05; **P<0.01.
DISCUSSION
We analyzed data from the ISCHEMIA trial in a high-risk SIHD population to understand the association between baseline participant characteristics and site factors (eg, medication provision and geographic region) with the odds of attaining trial goals of LDL-C <70 mg/dL and SBP <140 mm Hg after 1 year of participation. The principal findings of our study were that older age, lower baseline LDL-C, high-intensity statin use, and North American site location predicted LDL-C goal attainment at 1 year, whereas lower baseline SBP and enrollment at a North American site predicted SBP goal attainment. Importantly, women were nearly a third less likely to reach 1-year goals for LDL-C than men and also trended toward lower odds of SBP goal attainment at 1 year.
Goal Attainment at 1 Year
At 1 year, ≈50% and 75% of ISCHEMIA participants achieved targets for LDL-C and SBP, respectively. Prior studies reported the proportion of individuals in SIHD trials attaining OMT goals over time4,5,7 and observed a lower death rate associated with increased OMT goal attainment.4,7,9 However, this is the first analysis to describe predictors of OMT goal attainment over time within an ongoing randomized trial. The somewhat modest attainment of LDL-C and SBP goals at 1 year in ISCHEMIA highlight important issues. First, this is an interim analysis of LDL-C and SBP goal attainment in a multinational, multisite randomized trial and does not represent the final proportion of study participants reaching goals for LDL-C and SBP in ISCHEMIA. Second, our findings indicate a need for better strategies to optimize medical therapy in randomized clinical trials where patient and provider motivation to achieve OMT targets may be greater than that observed in routine clinical practice. By characterizing predictors of OMT goal attainment in the context of an international randomized strategy trial for the management of people with SIHD, the present study nevertheless provides important insights that may inform researchers and practitioners regarding which patients are more versus less likely to achieve cardiovascular risk factor control using similar medical therapies. Our findings may help guide future targeted efforts to improve OMT goal attainment in clinical trials through the use of central monitoring, uniform treatment algorithms, direct site contact, and involvement of trial leadership to maximize attainment of OMT goals.
We observed sex and racial disparities in attainment of the OMT goals at 1 year. A study of sex differences in prescribing practices and treatment targets for LDL-C and BP in the BARI 2D trial (Bypass Angioplasty Revascularization Investigation 2 Diabetes) demonstrated that women were less likely than men to achieve an LDL-C <100 mg/ dL during the trial.22 Prior studies have also demonstrated that compared with men, women with acute myocardial infarction receive less aggressive treatment with preventive therapies.11,23 Other studies have shown that racial/ ethnic minorities with coronary artery disease are less likely to receive guideline-directed medical therapy than non-Hispanic whites.24 In contrast, we observed that people of nonwhite race were more likely than white participants to achieve LDL-C goal at 1 year. This finding may reflect increased attention to secondary prevention in a clinical trial regardless of race/ethnicity, combined with undertreatment because of racial disparity before entering the clinical trial, thus increasing the proportion of 1-year LDL-C goal attainment for ISCHEMIA patients of nonwhite race. This finding calls for continued action to reduce cardiovascular risk factor treatment bias related to sex, race, and ethnicity in clinical and randomized trial populations alike.
Next, we found that older participants at baseline had greater adjusted odds of attaining the 1-year goal for LDL-C but lower odds of reaching the 1-year SBP goal. Possible explanations for this lesser success in achieving SBP control in older adults include age-related arterial stiffening, which tends to increase SBP with age, lesser tolerability of aggressive BP lowering, concern for excessive reduction of diastolic BP in coronary heart disease patients, and provider inertia. Despite evidence of comparable benefit for aggressive cardiovascular risk reduction for older compared with younger patients with SIHD, many older SIHD patients remain undertreated,25 particularly for attainment of BP goals.26 Age as a modifier of OMT goal attainment among patients with SIHD warrants further study. We did not observe an effect of medication provision or reimbursement on OMT goal attainment. This may be because of the relatively low proportion (≈30%) of ISCHEMIA sites that received or were reimbursed for medication.
Finally, we observed that compared with other regions, ISCHEMIA participants in North America had greater adjusted odds of reaching 1-year goals for both LDL-C and SBP. Prior studies have demonstrated country or region-specific differences in outcomes for multinational clinical trials,27,28 but why individuals from North America had improved odds of reaching 1-year goals for LDL-C and SBP compared with individuals from other regions is unknown. Potential explanations include regional differences in access to medications, medication adherence, and provider behavior. Further study of regional differences in risk factor goal attainment is needed.
Limitations
Although this study identifies predictors of observed 1-year LDL-C and SBP goal attainment in a large trial of patients with SIHD, there are several limitations. As with all observational analyses, unmeasured confounding is unavoidable, and variables unmeasured in our dataset may partially explain the increased odds of OMT goal attainment observed for people of older age or from North American sites. The large number of baseline factors tested for association with 1-year goal attainment increases the likelihood of detecting a potentially spurious association through chance alone. It is also likely that indication or severity bias resulted in participants with higher BP or LDL-C taking a greater number of medications or higher doses for risk factor control. This may have obscured our ability to detect an association between adherence at baseline attainment of 1-year goals for LDL-C and SBP. Additionally, to minimize site and participant burden, we used a limited self-assessment of adherence, which may have obscured our ability to detect an association between baseline adherence and attainment of LDL-C and SBP goals at 1 year. Although the definition and dose of high-intensity statins were prespecified in accordance with guidelines,24 to reduce participant and site burden, dosages of medications were not collected. The extent to which the observed regional variation in 1-year LDL-C and SBP goal attainment were due to differences in physician or health system practice patterns is unclear. Finally, we did not analyze behaviors such as dietary patterns or physical activity that may influence 1-year attainment of LDL-C and SBP goals.
Conclusions
In this clinical trial of patients with SIHD and moderatesevere inducible ischemia, we found that older age, male sex, high-intensity statin use, lower baseline LDL-C, and North American location predicted 1-year LDL-C goal attainment, whereas younger age, lower baseline SBP, and North American location predicted 1-year SBP goal attainment. The relatively modest rates of goal attainment in the setting of a rigorously conducted randomized trial emphasize the need to improve methods to achieve optimal risk factor control for patients with SIHD.
Supplementary Material
Acknowledgments
Sources of Funding
This work is supported by National Institute of Health grants U01HL105907, U01HL105462, U01HL105561, U01HL105565, and K23HL125991. This article refers to work supported by National Heart, Lung, and Blood Institute grant U01HL105907, U01HL105462, U01HL105561, U01HL105565; device donations from Abbott Vascular; Medtronic, Inc; St. Jude Medical, Inc; Volcano Corporation; and Omron Healthcare, Inc; medications provided by Amgen Inc; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corp; and by financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. The content of this article is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the United States Department of Health and Human Services.
Disclosures
Dr Spertus has received grant support from American College of Cardiology Foundation—PI Analytic Center and Bayer. He reports consultant fees from Bayer, Novartis, AstraZeneca, Janssen, Cytokinetics, MyoKardia, V-wave, Corvia, and United Healthcare Scientific Advisory Board. He serves a Board Member for Blue Cross Blue Shield of Kansas City, Health Outcomes Sciences, and Cardiovascular Outcomes. He owns Equity and Intellectual Property for Health Outcomes Sciences and Copyright to Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire. Dr Hochman reports being the principal investigator for the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) for which, in addition to support by National Heart, Lung, and Blood Institute grant, devices and medications were provided by Abbott Vascular; Medtronic, Inc; St. Jude Medical, Inc; Volcano Corporation; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corp; Omron Healthcare, Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. The other authors report no conflicts.
Contributor Information
Jonathan D. Newman, New York University School of Medicine.
Karen P. Alexander, Duke Clinical Research Institute, Durham, NC.
Xiangqiong Gu, Duke Clinical Research Institute, Durham, NC.
Sean M. O’Brien, Duke Clinical Research Institute, Durham, NC.
William E. Boden, VA New England Healthcare System, Boston, MA.
Sajeev C. Govindan, Government Medical College, Kerala, India.
Roxy Senior, Northwick Park Hospital-Royal Brompton Hospital, London, United Kingdom.
Nagaraja Moorthy, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.
Paulo C. Rezende, Heart Instituto do Coracao, University of Sao Paulo, Brazil.
Marcin Demkow, Coronary and Structural Heart Diseases Department, Institute of Cardiology, Warsaw, Poland.
Jose Luis Lopez-Sendon, Hospital Universitario La Paz, Idipaz, Madrid, Spain.
Olga Bockeria, National Research Center for Cardiovascular Surgery, Moscow, Russia.
Neeraj Pandit, Ram Manohar Lohia Hospital, Delhi, India.
Gilbert Gosselin, Montreal Heart Institute, QC, Canada.
Peter H. Stone, Brigham and Women’s Hospital, MA.
John A. Spertus, Saint Luke’s Mid America Heart Institute/UMKC, MO.
Gregg W. Stone, Columbia University Medical Center and the Cardiovascular Research Foundation, NY.
Jerome L. Fleg, National Institute of Health, NHLBI, MD.
Judith S. Hochman, New York University School of Medicine.
David J. Maron, Stanford University School of Medicine, CA.
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