INternational VErapamil SR-Trandolapril STudy Research Articles

Association of 1-Year Blood Pressure Variability With Long-term Mortality Among Adults With Coronary Artery Disease

Accumulating evidence indicates that higher blood pressure (BP) variability from one physician office visit to the next (hereafter referred to as visit-to-visit BP variability) is associated with poor outcomes. Short-term measurement (throughout 1 year) of visit-to-visit BP variability in high-risk older patients may help identify patients at increased risk of death. To evaluate whether short-term visit-to-visit BP variability is associated with increased long-term mortality risk. The US cohort of the International Verapamil SR-Trandolapril Study (INVEST), a randomized clinical trial of 16 688 patients aged 50 years or older with hypertension and coronary artery disease, was conducted between September 2, 1997, and December 15, 2000, with in-trial follow-up through February 14, 2003. The study evaluated a calcium antagonist (sustained-release verapamil plus trandolapril) vs β-blocker (atenolol plus hydrochlorothiazide) treatment strategy. Blood pressure measurement visits were scheduled every 6 weeks for the first 6 months and biannually thereafter. Statistical analysis was performed from September 2, 1997, to May 1, 2014. Visit-to-visit systolic BP (SBP) and diastolic BP variability during the first year of enrollment using 4 different BP variability measures: standard deviation, coefficient of variation, average real variability, and variability independent of the mean. All-cause death, assessed via the US National Death Index, beginning after the exposure assessment period through May 1, 2014. For the present post hoc analysis, long-term mortality data were available on 16 688 patients (9001 women [54%]; mean [SD] age, 66.5 [9.9] years; 45% White patients, 16% Black patients, and 37% Hispanic patients). During a mean (SD) follow-up of 10.9 (4.2) years, 5058 patients (30%) died. All 4 variability measures for SBP were significantly associated with long-term mortality after adjustment for baseline demographic characteristics and comorbidities. After comparison of lowest vs highest variability measure quintiles, the magnitude of the association with death remained statistically significant even after adjustment for baseline demographic characteristics and comorbidities (average real variability: adjusted hazard ratio [aHR], 1.18; 95% CI, 1.08-1.30; standard deviation: aHR, 1.14; 95% CI, 1.04-1.24; coefficient of variation: aHR, 1.15; 95% CI, 1.06-1.26; variability independent of the mean: aHR, 1.15; 95% CI, 1.05-1.25). The signal was stronger in women compared with men. Associations of diastolic BP variability measures with death were weaker than for SBP and were not significant after adjustment. This study suggests that, in a large population of older patients with hypertension and coronary artery disease, short-term visit-to-visit SBP variability was associated with excess long-term mortality, especially for women. Efforts to identify and minimize visit-to-visit SBP variability may be important in reducing excess mortality later in life. ClinicalTrials.gov Identifier: NCT00133692.

Optimal systolic blood pressure and reduced long-term mortality in older hypertensive women with prior coronary events – An analysis from INVEST☆

BackgroundHypertension and coronary artery disease (CAD) are a prevalent combination in older women, however limited data are available to guide blood pressure (BP) management. We hypothesized that older women with hypertension and CAD may not derive long-term benefit by achieving systolic BP (SBP) < 130 mmHg. MethodsWe analyzed long-term all-cause mortality data from the International Verapamil SR/Trandolapril Study (INVEST), stratified by risk attributable to clinical severity of CAD (women with prior coronary events of myocardial infarction or revascularization considered high risk, all others at low risk) and by age group (50–64 or ≥65 years). The prognostic impact of achieving mean in-trial SBP <130 (referent group) was compared with 130–139 and ≥ 140 mmHg using Cox proportional hazards, adjusting for demographic and clinical characteristics. ResultsSBPs <130, 130–139, and ≥140 were achieved in 2960, 3024, and 3232 women, respectively. Among high-risk women aged ≥65 years, those achieving SBP 130–139 mmHg had lower mortality up to 16.7 years later than those with SBP <130 (hazard ratio [HR] 0.81, 95% CI 0.69–0.96). High-risk women aged 50–64 achieving SBP 130–139 had a similar mortality risk as those with SBP <130 (HR 1.21, 95% CI 0.87–1.68), while those achieving SBP ≥140 mmHg had a higher mortality risk than SBP < 130 (HR 1.92, 95% CI 1.37–2.68). A similar pattern was observed among low-risk women ≥65 and <65 years old. ConclusionAmong women ≥65 years old with hypertension and prior coronary events, in-trial SBP between 130 and 139 mmHg was associated with lower mortality over the long term versus SBP <130 mmHg.

Systolic blood pressure, heart rate, and outcomes in patients with coronary disease and heart failure.

AimsData regarding the optimal systolic blood pressure (SBP) and heart rate (HR) for coronary artery disease (CAD) patients with hypertension and a history of heart failure (HF) are limited. Accordingly, using data from a large clinical trial, we investigated the association between SBP and heart rate and subsequent adverse outcomes in CAD patients with a history of HF, and we aimed to better understand how pre‐existing HF impacts outcomes among patients with CAD.Methods and resultsAmong 22 576 CAD patients enrolled in the INternational VErapamil SR‐Trandolapril STudy (INVEST), 1256 were identified with a history of physician‐diagnosed HF New York Heart Association (NYHA) Class 1–3 at entry. The primary outcome was the first occurrence of all‐cause death, myocardial infarction (MI), or stroke. Cox proportional‐hazards models adjusted for pre‐specified covariates were constructed to estimate risk among the HF cohort compared with a case‐matched sample from the non‐HF cohort. At a mean 2.5 years' follow‐up, those with prior HF had a higher risk of the primary outcome (hazard ratio (HR) 2.55, 95% confidence interval 2.30–2.83, P < 0.0001). Among those with history of HF, a low (<120 mmHg) or high (>140 mmHg) SBP and heart rate ≥ 85 b.p.m. were associated with increased risk for adverse outcomes, which persisted after covariate adjustment.ConclusionsIn patients with CAD, a physician diagnosis of HF at baseline portended a higher risk for death, MI, or stroke than in those without an HF history. Achieving SBP of 120–140 mmHg and heart rate < 85 b.p.m. was associated with a better outcome in patients with known HF and CAD.

P5730Do hypertensive women with coronary artery disease benefit from lowering systolic blood pressure under 130 mmHg? Long-term mortality in the INternational VErapamil SR-trandolapril STudy (INVEST)

Abstract Background Hypertension (HTN) and coronary artery disease (CAD) are a prevalent combination in women, however limited data are available to guide blood pressure (BP) management. We hypothesize older women with HTN and CAD may not derive the same prognostic benefit from systolic BP (SBP) lowering &lt;130 mmHg. Purpose To investigate the long-term mortality implications of different achieved SBP levels in hypertensive women with CAD. Methods Long-term, all-cause mortality data were analyzed for 9216 women, stratified by risk attributable to clinical severity of CAD (women with prior myocardial infarction or revascularization considered at high, all others at low risk) and by age (50 - &lt;65 or ≥65 yo). The prognostic impact of achieving mean in-trial SBP &lt;130 (referent group) was compared with 130 to &lt;140 and ≥140 mmHg using Cox proportional hazards, adjusting for demographic and clinical characteristics. Results During 108,838 person-years of follow-up, 2945 deaths occurred. High risk women (n=3011) had increased long-term mortality in comparison to low risk women (n=6205) (adjusted HR 1.38, CI 1.28–1.5, p&lt;0.001). Within risk groups, crude mortality percentages decreased according to BP values (table). As expected, high risk women were more likely to be ≥65 yo (68.68% vs. 50.51%, p&lt;0.0001) or have SBP ≥140 mmHg (43.08% vs. 31.18%, p&lt;0.0001). In adjusted analyses, an SBP ≥140 mmHg was associated with worse outcomes than SBP &lt;130 mmHg in the entire cohort (HR 1.3, CI 1.2–1.5, p&lt;0.0001) and when stratifying by risk (low risk group, HR = 1.47, CI 1.28–1.7, p&lt;0.0001; high risk group, HR = 1.71, CI 1.01–1.35, p=0.03). In analyses stratified by age and risk, women ≥65 years and at high risk had decreased mortality in the 130 - &lt;140 SBP category vs. &lt;130 mmHg (HR 0.812, 95% CI 0.689–0.957, p=0.0133; figure). Women and deaths by risk and SBP group Group SBP category Women (n) Mortality (n) Mortality (%) High risk &lt;130 773 338 44 130–&lt;140 941 414 44 ≥140 1297 694 54 Low risk &lt;130 2187 390 18 130–&lt;140 2083 451 22 ≥140 1935 658 34 SBP = systolic blood pressure; n = number; % = percent per each group. Mortality adjusted HRs Conclusion In women ≥65 yo with hypertension and prior myocardial infarction and/or coronary revascularization enrolled in INVEST, a SBP between 130 to &lt;140 mmHg was associated with lower all-cause, long-term mortality versus SBP &lt;130 mmHg. Acknowledgement/Funding The main INVEST (International Verapamil [SR]/Trandolapril Study) was funded by grants from BASF Pharma, Ludwigshafen, Germany; Abbott Laboratories, A

Risk and Blood Pressure Control Rates Across the Spectrum of Coronary Artery Disease in Hypertensive Women: An Analysis from The INternational VErapamil SR-Trandolapril STudy (INVEST).

Background: Hypertension is a major modifiable risk factor for coronary artery disease (CAD), the main cause of death in women. While association between the two is frequent, limited data exist regarding the feasibility of blood pressure (BP) management and outcomes in women across the spectrum of CAD. Accordingly, we analyzed patient characteristics, BP control rates, and outcomes among hypertensive women with CAD, enrolled in The INternational VErapamil SR-trandolapril STudy (INVEST). Methods: The 11,770 hypertensive women with CAD in INVEST were studied based on presence (n = 3,879) or absence (n = 7,891) of history of myocardial infarction (MI) or coronary revascularization, to evaluate outcomes across risk groups based on severity of CAD. Results: Women with prior MI or revascularization were older (4 years, p < 0.0001), were predominantly white (62% vs. 29%), and had more associated comorbidities than women without these events. At 24 months, JNC VI (sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) BP control rates were lower in women with prior MI or revascularization (57% vs. 64%, p < 0.0001), despite more intensive antihypertensive therapy. The primary outcome (first occurrence of all-cause death, nonfatal MI, or nonfatal stroke) was also more frequent in women with prior MI or revascularization (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.34-1.74), who were 42% more likely to die (adjusted HR 1.42; 95% CI 1.22-1.64), twice as likely to have a nonfatal MI (adjusted HR 2.4, 95% CI 1.64-3.51), and 56% more likely to have a nonfatal stroke (adjusted HR 1.56, 95% CI 1.1-2.21). Conclusions: In a prospective, multinational cohort of hypertensive women with CAD, those with prior MI or revascularization comprised a group at higher risk for death, nonfatal MI, and nonfatal stroke, and were less likely to have their BP controlled, despite more aggressive therapy. The feasibility and benefit of reducing BP to <130/80 mmHg in women, particularly with more severe CAD, warrant further investigation.

Genetic Variants Associated With Uncontrolled Blood Pressure onThiazide Diuretic/β-Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses)and INVEST (International Verapamil-SR Trandolapril Study) Trials.

BackgroundThe majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β‐blocker.Methods and ResultsA genome‐wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P<1.0E‐05) were tested for replication in an external cohort, INVEST (International Verapamil‐SR Trandolapril study). We also examined genome‐wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69–3.88, P=8.64E‐06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35–2.57, P=0.001) and approached genome‐wide significance in the meta‐analysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63–2.86, P=8.60E‐08). Other genes in the region surrounding rs261316 (ALDH1A2) include AQP9 and LIPC.ConclusionsA single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β‐blocker combination.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.

CES1P1 variant -816A>C is not associated with hepatic carboxylesterase 1 expression and activity or antihypertensive effect of trandolapril.

The majority of angiotensin-converting enzyme inhibitors (ACEIs) are synthesized as ester prodrugs that must be converted to their active forms in vivo in order to exert therapeutic effects. Hepatic carboxylesterase 1 (CES1) is the primary enzyme responsible for the bioactivation of ACEI prodrugs in humans. The genetic variant -816A>C (rs3785161) is a common variant located in the promoter region of the CES1P1 gene. Previous studies report conflicting results with regard to the association of this variant and therapeutic outcomes of CES1 substrate drugs. The purpose of this study was to determine the effect of the variant -816A>C on the activation of the ACEI prodrug trandolapril in human livers and the blood pressure (BP)-lowering effect of trandolapril in hypertensive patients. The -816A>C genotypes and CES1 expression and activity on trandolapril activation were determined in 100 individual human liver samples. Furthermore, the association of the -816A>C variant and the BP lowering effect of trandolapril was evaluated in hypertensive patients who participated in the International Verapamil SR Trandolapril Study (INVEST). Our in vitro study demonstrated that hepatic CES1 expression and activity did not differ among different -816A>C genotypes. Moreover, we were unable to identify a clinical association between the BP lowering effects of trandolapril and -816A>C genotypes. We conclude that the -816A>C variant is not associated with interindividual variability in CES1 expression and activity or therapeutic response to ACEI prodrugs.

Target Blood Pressure in Patients with Diabetes: Asian Perspective.

Recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) trial enrolled 4733 participants with type 2 diabetes and randomized them to a target systolic blood pressure (SBP) of less than 120 mm Hg or 140 mm Hg. Despite the significant difference in the achieved SBP, there was no significant difference in the incidence of primary outcomes. Based on this evidence, the target SBP for diabetics has been revised in the majority of major guidelines. However, there is a steeper association between SBP and stroke in Asians than other ethnicities, with stroke being the leading cause of cardiovascular mortality. This suggests that target BP in the Asian region should be tailored towards prevention of stroke. In the ACCORD study, the intensive BP treatment was associated with significant reductions in both total stroke and non-fatal stroke. The results from the ACCORD study are supported by a subgroup analysis from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, which showed that, in diabetic patients, the risk of stroke continues to decrease to a SBP value of 115 mm Hg with no evidence of J curve. As diabetes is highly associated with underlying coronary artery disease, there is a justified concern for adverse effects resulting from too much lowering of BP. In a post hoc analysis of 6400 diabetic subjects enrolled in the International Verapamil SR-Trandolapril (INVEST) study, subjects with SBP of less than 110 mm Hg were associated with a significant increase in all-cause mortality. In the ONTARGET study, at any levels of achieved SBP, diastolic blood pressure (DBP) below 67 mm Hg was associated with increased risk for cardiovascular outcomes. As such, a prudent approach would be to target a SBP of 130–140 mm Hg and DBP of above 60 mm Hg in diabetics with coronary artery disease. In conclusion, hypertension, in association with diabetes, has been found to be significantly correlated with an elevated risk for cardiovascular events. As the association between stroke and BP is stronger in Asians, compared to other ethnicities, consideration should be given for a target BP of 130/80 mm Hg in Asians.

Abstract 15465: Precision Medicine Approach to Resistant Hypertension: Genetic Markers of Resistant Hypertension Through a Genome-wide Association Study (GWAS) in the Secondary Prevention of Subcortical Strokes (SPS3)

Introduction: Resistant hypertension (RHTN), a blood pressure (BP) ≥140/90 mm Hg despite ≥ 3 antihypertensive drugs or BP &lt; 140/90 mm Hg using ≥ 4 drugs, is associated with increased incidence of adverse cardiovascular outcomes, especially stroke. Hypothesis and objective: We hypothesize common variants exist in the genes regulating BP response and may lead to RHTN in some patients. Methods: A discovery cohort of hypertensive participants were included as cases (as defined above) or controls (N=719; 263 whites, 322 Hispanics, and 134 African Americans) from SPS3-GENES. They were genotyped on the Illumina Omni 5 Exome chip. Multiple logistic regression analysis was conducted separately in each race using an additive genetic model, adjusting for predictors for RHTN, principle components for ancestry and BP target treatment arms. Results from the 3 racial groups were combined using meta-analysis with inverse-variance weighting, with the hypothesis that functional variants are consistent across races. The associations of seven SNPs that met the suggestive level of association (p &lt;1 x10-5) in the SPS3 meta-analysis were tested for replication in 1,194 participants (657 whites, and 537 Hispanics) from the INternational VErapamil-SR trandolapril STudy GENEtic Substudy (INVEST-GENES). Bonferroni adjusted p was set at 0.007 to correct for multiple comparisons. Combined meta-analysis between INVEST and SPS3 was conducted for replicated SNPs or SNPs that had consistent association in the two cohorts with a nominal significance. Results: A missense SNP (rs3766160; Asp114Asn) in CELA2B was associated with increased risk of RHTN in SPS3 (Combined OR=1.8, p=6x10-6)). The same SNP replicated in INVEST (Combined OR=1.3, p=0.004; INVEST/SPS3 meta-p=4.5x10-7). An intronic SNP rs3789592 in strong linkage disequilibrium (r2=0.98) with a missense SNP (rs1049434; Asp490Glu) in SLC16A1 was associated with RHTN in SPS3 (Combined OR=2.0, p=7.6x10-7) and had a consistent association in INVEST (Combined OR=1.2, p=0.048; INVEST/SPS3 meta-p=7.6x10-7). Conclusion: Genetic loci in CELA2B, SLC16A1 were identified and confirmed for association in two cohorts. These associations, if further validated may help identify those patients at risk for RHTN.

PTPRD gene associated with blood pressure response to atenolol and resistant hypertension.

The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the β-blocker atenolol. Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114). In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 × 10 and P = 5.9 × 10, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 × 10). rs12346562 had a similar trend in association with response to bisoprolol (a different β-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 × 10). PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.

Effects of verapamil SR and atenolol on 24-hour blood pressure and heart rate in hypertension patients with coronary artery disease: an international verapamil SR-trandolapril ambulatory monitoring substudy.

Elevated nighttime blood pressure (BP) and heart rate (HR), increased BP and HR variability, and altered diurnal variations of BP and HR (nighttime dipping and morning surge) in patients with systemic hypertension are each associated with increased adverse cardiovascular events. However, there are no reports on the effect of hypertension treatment on these important hemodynamic parameters in the growing population of hypertensive patients with atherosclerotic coronary artery disease (CAD). This was a pre-specified subgroup analysis of the INternational VErapamil SR-Trandolapril STudy (INVEST), which involved 22,576 clinically stable patients aged ≥50 years with hypertension and CAD randomized to either verapamil SR- or atenolol-based hypertension treatment strategies. The subgroup consisted of 117 patients undergoing 24-hour ambulatory monitoring at baseline and after 1 year of treatment. Hourly systolic and diastolic BP (SBP and DBP) decreased after 1 year for both verapamil SR- and atenolol-based treatment strategies compared with baseline (P<0.0001). Atenolol also decreased hourly HR (P<0.0001). Both treatment strategies decreased SBP variability (weighted standard deviation: P = 0.012 and 0.021, respectively). Compared with verapamil SR, atenolol also increased the prevalence of BP and HR nighttime dipping among prior non-dippers (BP: OR = 3.37; 95% CI: 1.26 – 8.97; P = 0.015; HR: OR = 4.06; 95% CI: 1.35-12.17; P = 0.012) and blunted HR morning surge (+2.8 vs. +4.5 beats/min/hr; P = 0.019). Both verapamil SR- and especially atenolol-based strategies resulted in favorable changes in ambulatory monitoring parameters that have been previously associated with increased adverse cardiovascular events.Trial RegistrationClinicaltrials.gov; NCT00133692

2014 Eighth Joint National Committee Panel Recommendation for Blood Pressure Targets Revisited: Results From the INVEST Study

BackgroundThe 2014 Eighth Joint National Committee panel recommendations for management of high blood pressure (BP) recommend a systolic BP threshold for initiation of drug therapy and a therapeutic target of <150 mm Hg in those ≥60 years of age, a departure from prior recommendations of <140 mm Hg. However, it is not known whether this is an optimal choice, especially for the large population with coronary artery disease (CAD). ObjectivesThis study sought to evaluate optimal BP in patients ≥60 years of age. MethodsPatients 60 years of age or older with CAD and baseline systolic BP >150 mm Hg randomized to a treatment strategy on the basis of either atenolol/hydrochlorothiazide or verapamil-SR (sustained release)/trandolapril in INVEST (INternational VErapamil SR Trandolapril STudy) were categorized into 3 groups on the basis of achieved on-treatment systolic BP: group 1, <140 mm Hg; group 2, 140 to <150 mm Hg; and group 3, ≥150 mm Hg. Primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary outcomes were all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, nonfatal stroke, heart failure, or revascularization, tabulated separately. Outcomes for each group were compared in unadjusted and multiple propensity score–adjusted models. ResultsAmong 8,354 patients included in this analysis with an accumulated 22,308 patient-years of follow-up, 4,787 (57%) achieved systolic BP of <140 mm Hg (group 1), 1,747 (21%) achieved systolic BP of 140 to <150 mm Hg (group 2), and 1,820 (22%) achieved systolic BP of ≥150 mm Hg (group 3). In unadjusted models, group 1 had the lowest rates of the primary outcome (9.36% vs. 12.71% vs. 21.32%; p < 0.0001), all-cause mortality (7.92% vs. 10.07% vs. 16.81%; p < 0.0001), cardiovascular mortality (3.26% vs. 4.58% vs. 7.80%; p < 0.0001), MI (1.07% vs. 1.03% vs. 2.91%; p < 0.0001), total stroke (1.19% vs. 2.63% vs. 3.85%; p <0.0001), and nonfatal stroke (0.86% vs 1.89% vs 2.86%; p<0.0001) compared with groups 2 and 3, respectively. In multiple propensity score–adjusted models, compared with the reference group of <140 mm Hg (group 1), the risk of cardiovascular mortality (adjusted hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.01 to 1.77; p = 0.04), total stroke (adjusted HR: 1.89; 95% CI: 1.26 to 2.82; p = 0.002) and nonfatal stroke (adjusted HR: 1.70; 95% CI: 1.06 to 2.72; p = 0.03) was increased in the group with BP of 140 to <150 mm Hg, whereas the risk of primary outcome, all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, and nonfatal stroke was increased in the group with BP ≥150 mm Hg. ConclusionsIn hypertensive patients with CAD who are ≥60 years of age, achieving a BP target of 140 to <150 mm Hg as recommended by the JNC-8 panel was associated with less benefit than the previously recommended target of <140 mm Hg.

Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension

Resistant hypertension (res-HTN) is a challenging problem, but little is known of res-HTN in patients with coronary artery disease (CAD). In this post-hoc INternational VErapamil SR-Trandolapril STudy (INVEST) analysis, we assessed prevalence, predictors, and impact on outcomes of res-HTN in CAD patients with hypertension. Participants (n=17190) were divided into three groups according to achieved blood pressure (BP): controlled (BP <140/90 mmHg on three or fewer drugs); uncontrolled (BP ≥ 40/90 mmHg on two or fewer drugs); or resistant (BP ≥ 40/90 mmHg on three drugs or any patient on at least four drugs). The prevalence of res-HTN was 38%: significant predictors of res-HTN included heart failure [odds ratio (OR) 1.73], diabetes (OR 1.63), Black race (OR 1.50), and US residence (OR 1.50). Compared with controlled HTN, res-HTN had multivariate-adjusted association with higher risk of adverse outcomes {first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke [hazard ratio 1.27, 95% confidence interval (CI) 1.13-1.43], and individual outcomes of all-cause death (hazard ratio 1.29, 95% CI 1.13-1.48), cardiovascular mortality (hazard ratio 1.47, 95% CI 1.21-1.78), and nonfatal stroke (hazard ratio 1.61, 95% CI 1.17-2.22), but not nonfatal myocardial infarction (hazard ratio 0.98, 95% CI 0.72-1.34)}. Adverse outcomes, except nonfatal stroke, did not differ in patients with res-HTN compared to uncontrolled HTN. Res-HTN is common in patients with CAD and hypertension, associated with poor prognosis, and linked with a number of conditions. Emphasis should be placed on recognizing those at risk for res-HTN and future studies should examine whether more aggressive treatment of res-HTN improves outcomes.

Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes

Thiazide diuretics have been associated with increased risk for new onset diabetes (NOD), but pharmacogenetic markers of thiazide-induced NOD are not well studied. Single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2) represent the strongest and most reproducible genetic associations with diabetes. We investigated the association of tag SNPs in TCF7L2 with thiazide-induced NOD. We identified cases that developed NOD and age, sex, and race/ethnicity-matched controls from the INternational VErapamil SR-Trandolapril STudy (INVEST). INVEST compared cardiovascular outcomes between two antihypertensive treatment strategies in ethnically diverse patients with hypertension and coronary artery disease. We genotyped 101 TCF7L2 tag SNPs and used logistic regression to test for pharmacogenetic (SNP×hydrochlorothiazide treatment) interactions. Permuted interaction P values were corrected with the PACT test and adjusted for diabetes-related variables. In INVEST whites, we observed three TCF7L2 SNPs with significant SNP×treatment interactions for NOD. The strongest pharmacogenetic interaction was observed for rs7917983 [synergy index 3.37 (95% CI 1.72-6.59), P=5.0×10, PACT=0.03], which was associated with increased NOD risk in hydrochlorothiazide-treated patients [odds ratio 1.53 (1.04-2.25), P=0.03] and decreased NOD risk in non hydrochlorothiazide-treated patients [odds ratio 0.48 (0.27-0.86), P=0.02]. The TCF7L2 SNP rs4506565, previously associated with diabetes, showed a similar, significant pharmacogenetic association. Our results suggest that hydrochlorothiazide treatment is an environmental risk factor that increases diabetes risk beyond that attributed to TCF7L2 variation in white, hypertensive patients. Further study and replication of our results is needed to confirm pharmacogenetic influences of TCF7L2 SNPs on thiazide-induced NOD.

Pharmacogenomic Association of Nonsynonymous SNPs in SIGLEC12 , A1BG , and the Selectin Region and Cardiovascular Outcomes

We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a β-blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)×treatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10(-5)). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42-0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08-1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.

Phase II Clinical Research Design in Cardiology

Clinical trials demonstrate the best of medical expertise and epidemiological elegance. From the simple building blocks of contemporaneous control groups, randomization, and blinding, they assemble a clear picture of the nature of the treatment-effect relationship. This accomplishment has earned them the star ascendant position in cardiovascular research. Their advantage was demonstrated with Bradford Hill’s work on streptomycin, and as knowledge of the pathogenesis of atherosclerotic disease produced possibilities for new treatments, cardiovascular researchers applied this new research tool to identify effective therapies in a sequential approach (Figure 1). Figure 1. The traditional phases of clinical trials. *The study takes place before Food and Drug Administration approval. This work accelerated with clinical trials demonstrating treatment benefits for chronic diseases such as hypertension,1,2 lipid abnormalities,3,4 and heart failure,5,6 cementing their role in identifying new therapies to prevent the sequela of cardiovascular disease in vulnerable populations. However, the limitations of early clinical trial interpretation also appeared. The findings of the Multiple Risk Factor Intervention Trial (MRFIT),7 the International Verapamil SR/Trandolapril Study (INVEST),8,9 the Early Versus Late Intervention Trial With Estradiol (ELITE),7,10 the Cardiac Arrhythmia Suppression Trial (CAST),11,12 and the US Carvedilol program controversy13–19 together served to undermine the confidence of cardiologists in the interpretation of clinical trial results. Thought leaders in the field identified the interpretation problem (ie, the hyperreliance on P values to reflect positive results for any analysis in a clinical trial) and called for a fundamental change in the design and analysis of clinical trials. Subsequent work produced the following clinical trials principles: (1)There should be clear and prospective declaration in the written protocol about all important aspects of the clinical trial with particular emphasis on the end points …

Genetic Variation in PEAR1 Is Associated With Platelet Aggregation and Cardiovascular Outcomes

BACKGROUND- Aspirin or dual antiplatelet therapy with aspirin and clopidogrel is a standard therapy for patients who are at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known. METHODS AND RESULTS- We measured ex vivo platelet aggregation before and after dual antiplatelet therapy in individuals (n=565) from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and conducted a genome-wide association study of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in 2 independent aspirin-treated cohorts: 227 percutaneous coronary intervention patients and 1000 patients of the International Verapamil SR/Trandolapril Study (INVEST) Genetic Substudy (INVEST-GENES). Results from the genome-wide association study revealed a strong association between single-nucleotide polymorphisms on chromosome 1q23 and post-dual antiplatelet therapyplatelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with dual antiplatelet therapy response (P=7.66×10(-9)). In white and black patients undergoing percutaneous coronary intervention, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared with GG homozygotes (hazard ratio, 2.62; 95% confidence interval, 0.96-7.10; P=0.059; and hazard ratio, 3.97; 95% confidence interval, 1.10-14.31; P=0.035, respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared with GG homozygotes (odds ratio, 2.03; 95% confidence interval, 1.01-4.09; P=0.048). CONCLUSION- Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin alone or in combination with clopidogrel. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00799396 and NCT00370045.

Lack of association of the HMGA1 IVS5-13insC variant with type 2 diabetes in an ethnically diverse hypertensive case control cohort.

BackgroundRecently, the high-mobility group A1 gene (HMGA1) variant IVS5-13insC has been associated with type 2 diabetes, but reported associations are inconsistent and data are lacking in Hispanic and African American populations. We sought to investigate the HMGA1-diabetes association and to characterize IVS5-13insC allele frequencies and linkage disequilibrium (LD) in 3,070 Caucasian, Hispanic, and African American patients from the INternational VErapamil SR-Trandolapril STudy (INVEST).MethodsINVEST was a randomized, multicenter trial comparing two antihypertensive treatment strategies in an ethnically diverse cohort of hypertensive, coronary artery disease patients. Controls, who were diabetes-free throughout the study, and type 2 diabetes cases, either prevalent or incident, were genotyped for IVS5-13insC using Taqman®, confirmed with Pyrosequencing and Sanger sequencing. For LD analysis, genotyping for eight additional HMGA1 single nucleotide polymorphisms (SNPs) was performed using the Illumina® HumanCVD BeadChip. We used logistic regression to test association of the HMGA1 IVS5-13insC and diabetes, adjusted for age, gender, body mass index, and percentage European, African, and Native American ancestry.ResultsWe observed IVS5-13insC minor allele frequencies consistent with previous literature in Caucasians and African Americans (0.03 in cases and 0.04 in controls for both race/ethnic groups), and higher frequencies in Hispanics (0.07 in cases and 0.07 in controls). The IVS5-13insC was not associated with type 2 diabetes overall (odds ratio 0.98 [0.76-1.26], p=0.88) or in any race/ethnic group. Pairwise LD (r2) of IVS5-13insC and rs9394200, a SNP previously used as a tag SNP for IVS5-13insC, was low (r2=0.47 in Caucasians, r2=0.25 in Hispanics, and r2=0.06 in African Americans). Furthermore, in silico analysis suggested a lack of functional consequences for the IVS5-13insC variant.ConclusionsOur results suggest that IVS5-13insC is not a functional variant and not associated with type 2 diabetes in an ethnically diverse, hypertensive, coronary artery disease population. Larger, more adequately powered studies need to be performed to confirm our findings.Trial registrationclinicaltrials.gov (NCT00133692)

G protein receptor kinase 4 polymorphisms

G protein–coupled receptor kinases (GRKs) are important regulatory proteins for many G protein–coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized that 3 nonsynonymous GRK4 single-nucleotide polymorphisms, R65L (rs2960306), A142V (rs1024323), and A486V (rs1801058), would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long-term cardiovascular outcomes (all-cause death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR–based antihypertensive strategy. GRK4 single-nucleotide polymorphisms were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In whites and blacks, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (−9.1±6.8 versus −6.8±7.1 versus −5.3±6.4 mm Hg in participants with 0, 1, and 2 copies of 65L-142V, respectively; P =0.0088). One thousand four hundred sixty participants with hypertension and coronary artery disease from the INternational VErapamil SR/Trandolapril STudy (INVEST) were genotyped, and variant alleles of all 3 GRK4 single-nucleotide polymorphisms were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (odds ratio, 2.29 [1.48–3.55]; P =0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest that the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R homozygotes, suggesting a potential interaction between these 2 genes.

Association of KCNJ1 variation with change in fasting glucose and new onset diabetes during HCTZ treatment

Thiazide-induced potassium loss may contribute to new onset diabetes (NOD). KCNJ1 encodes a potassium channel and one study observed that a KCNJ1 single-nucleotide polymorphism (SNP) was associated with changes in fasting glucose (FG) during hydrochlorothiazide (HCTZ) treatment. We used linear regression to test association of KCNJ1 SNPs and haplotypes with FG changes during HCTZ treatment in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We used logistic regression to test association of KCNJ1 variation with NOD in HCTZ-treated patients from the International Verapamil SR Trandolapril Study (INVEST). Multivariate regression analyses were performed by race/ethnicity with false discovery rate (FDR) correction. In PEAR blacks, a KCNJ1 SNP was associated with increased FG during HCTZ treatment (beta=8.47, P(FDR)=0.009). KCNJ1 SNPs and haplotypes were associated with NOD risk in all INVEST race/ethnic groups (strongest association: odds ratio 2.14 (1.31-3.53), P(FDR)=0.03). Our findings support that KCNJ1 variation is associated with HCTZ-induced dysglycemia and NOD.