American College of Cardiology 2013 Abstracts Explore PGx, Prognostic Strategies for Cardiac Conditions

Originally published March 12.

The American College of Cardiology held its annual meeting in San Francisco March 9 - 11. The following abstracts presented at the meeting highlight the use of pharmacogenomics to guide treatment for cardiac conditions or the use of genomic or proteomic factors to gauge outcomes in patients with various cardiac conditions.

Researchers led by Shweta Motiwala from Massachusetts General Hospital hypothesized that insulin-like growth factor binding protein 7 may be associated with cardiac outcomes, prognosis, and remodeling in chronic heart failure patients.

In the study, Motiwala et al. followed 142 patients with left ventricular systolic dysfunction through 908 visits over approximately 10 months. LVSD occurs when the heart is unable to pump out blood normally and as a result blood accumulates in the veins and lungs. Motiwala and colleagues used the amount of time patients had IGFBP7 levels less than or equal to 102.9 pg/mL during the study period and their change in IGFBP7 values from baseline to their final visit to determine their risk of adverse cardiovascular events and to assess echocardiographic parameters of left ventricular remodeling.

The study showed patients who experienced CV events had higher medical IGFBP7 values at baseline and at three months. "Duration of time spent with IGFBP7 [levels less than or equal to] 102.9 pg/mL was associated with a lower rate of cardiovascular events and independently predicted fewer CV events," the study authors wrote in the abstract. Among patients that always had low IGFBP7 levels, 28 percent experienced cardiovascular events while around 61 percent of patients who always had high levels experienced cardiovascular events. Additionally, researchers noted that an increase in IGFBP7 was associated with an increase in left ventricular volume.

In the study, researchers used beta-blockers and loop diuretics to reduce patients' IGFBP7 levels. "In chronic heart failure due to LVSD, serial measurement of IGFBP7 provides independent prognostic information and may predict deleterious myocardial remodeling," Motiwala et al. concluded.

CYP2C19 Loss-of-Function Alleles Are Not Associated with Clinical Outcome of Clopidogrel Therapy in Patients Treated with Newer-Generation Drug-Eluting Stents

Researchers led by Ik Jun Choi of Catholic Medical Center in Seoul, South Korea, looked at the potential impact of newer drug-eluting stents in patients with CYP2C19 loss-of-function alleles.

In the study, Choi et al. looked at more than 2,000 patients who received a percutaneous coronary intervention either with first-generation drug-eluting stents or newer-generation drug-eluting stents. The primary endpoint in the study was to compare major cardiac and cerebrovascular events (including all-cause death, non-fatal myocardial infarction, or stroke during a one-year follow-up period) among patients in the two arms.

The study authors reported that CYP2C19 loss-of-function alleles were linked with higher major cardiac and cerebrovascular events in patients treated with first-generation drug-eluting stents. But these markers were not associated with the primary outcome in those treated with newer drug-eluting stents. Additionally, Choi et al. reported no difference in platelet reactivity between the two patient groups.

"Multivariate analysis demonstrated that there was no significance in newer-generation drug-eluting stents, although CYP2C19 LOF alleles were an independent predictor of major cardiac and cerebrovascular events in patients with first-generation drug-eluting stents," the researchers reported.

Based on this data, Choi et al. concluded that "CYP2C19 loss-of-function alleles may not affect clinical outcome of clopidogrel therapy in patients treated with newer-generation drug-eluting stents."

Using Genetic Testing to Guide Warfarin Initiation Dosing and Decreasing Time to Achieve Therapeutic INR

Researchers led by Craig McCotter of St. Francis Heart Hospital in Greenville, SC, compared how quickly patients without CYP2C9 and VKORC1 polymorphisms reached therapeutic international normalized ratio while on the anticoagulant warfarin compared to patients in the hospital with these mutations that impact their ability to respond to the drug.

After testing patients in St. Francis Heart Hospital for polymorphisms in these two enzymes by Iverson Genetics' Warfarin GenoSTAT test, McCotter et al. grouped patients into four arms: the control group didn't have these gene mutations; one arm enrolled patients who had CYP2C9 polymorphisms only; the third arm included patients who had polymorphisms in VKORC1; and the last group included those who had polymorphisms in both enzymes. Patients who harbored gene mutations had their warfarin doses determined according to warfarindosing.org.

In the control group, therapeutic INR was reached after an average of 100.11 ± 81.90 hours. Comparatively, those with only CYP2C9 polymorphisms, only VKORC1 polymorphisms, and both types of mutations reached therapeutic INR after an average of 58.61 ± 29.84 hours, 93.6 ± 41.85 hours, and 49.92 ± 23.53 hours, respectively.

Previous studies have reported that the national average to reach a therapeutic INR in patients taking warfarin without the help of genetic testing is 168.36 ± 73.44 hours. Meanwhile, the average time to reach therapeutic INR in a pharmacist-managed group was 93.6 hours, the study authors noted. "The data collected in this study shows an average time of only 73.21 ± 56.517 hours until therapeutic INR was achieved," the researchers reported in their abstract.

"Inconsistency in the response to warfarin is complex; it includes genetic polymorphisms in CYP2C9, VKORC1, and possibly other influences still being researched," McCotter and colleagues concluded in their abstract. "Genetically customized warfarin doses provide an appealing replacement to the 'average' effective dose method."

Prognostic Impact of Beta-Adrenergic Receptor Gene Polymorphisms on Secondary Prevention after Acute Myocardial Infarction in the PCI Era

Sen Matsumoto and others from the Osaka University Graduate School of Medicine investigated the prognostic impact of ADRB gene polymorphisms in the secondary prevention setting of acute myocardial infarction. In order to do so Matusmoto et al. genotyped more than 3,000 patients enrolled in the Osaka Acute Coronary Insufficiency Study between 1998 and 2008 for ADRB1, ADRB2, and ADRB3 gene polymorphisms.

The researchers gauged the prognostic impact of these polymorphisms alone and in combination by multivariate Cox regression, and also examined the pharmacogenetic interactions with β-blockers, renin angiotensin system inhibitors, and statins. The endpoints of interest were all-cause death and a composite of death and heart failure leading to hospitalization.

After more than 1,756 days, the researchers noted there were 231 deaths and 193 heart failures. The study investigators did not find a significant association between any one polymorphism and endpoint. "However, the combination of ADRB1 389Arg/Arg, ADRB1 49Ser/Gly or 49Gly/Gly, ADRB2 27Gln/Gln and ADRB2 -19Cys/Cys was significantly associated with an increased risk of all-cause death and the composite endpoint," Matsumoto et al. reported.

While the analysis looking into pharmacogenetic interactions did not reveal that any of the medications positively affected the risk haplotype, the researchers found that beta-blockers "might have adverse prognostic impacts on the risk haplotype."

As a result, Matsumo and colleagues concluded that "not any single, but a combination of the ADRB gene polymorphisms affected prognosis in post-acute myocardical infarction patients. Importantly, beta-blockers might have adverse effects in patients with the risk haplotype, although further study is warranted to confirm the results."

An Investigation into the Effect of Cytochrome P450 (CYP) 2D6 Genotype on Pharmacokinetics, Pharmacodynamics and Outcomes during Metoprolol CR/XL Therapy in a Heart Failure Cohort: A MERIT-HF Sub-Study

Jonathan Adam Batty of the Leeds Institute of Genetics, Health, and Therapeutics and members of the MERIT-HG Study Group investigated the impact of CYP2D6 genotypes in heart failure patients treated with a high-dose selective beta 1 adrenergic receptor antagonist, called metoprolol.

Previously conducted pharmacogenetic studies involving low-dose metoprolol have shown that the drug is metabolized by CYP2D6 enzyme, which in turn yields varying pharmacokinetic and pharmacodynamic responses in patients.

In this study, Batty et al. looked for CYP2D6 alleles among the 600 patients previously enrolled in the MERIT-HF trial, and then conducted S-metoprolol serum assays after 90 days to investigate the pharmacokinentic effects of the drug. Researchers drew data from the MERIT-HF study to note the pharmacodynamic effects and the clinical outcomes.

Based on whether patients had the CYP2D6 *4 allele, Batty et al. identified study participants as either extensive, intermediate, or poor metabolizers of metoprolol. Researchers found that the mean dose-/weight-adjusted plasma metoprolol concentrations were 2.12-fold and 4.47-fold greater in the intermediate and poor metabolizers as compared to the extensive metabolizer group. When pharmacodynamics were considered, the researchers reported that metoprolol "induced greater reductions in mean standard deviation heart rate and diastolic blood pressure." But this effect was not present at the maximal metoprolol dose. Additionally, researchers did not observe a genotypic difference in achieving the target metoprolol dose of 200 mg per day.

In the study, a greater proportion of patients in the combined poor metabolizer/intermediate metabolizer group achieved a heart rate of less than 60 beats per minute compared to the extensive metabolizer group. "CYP2D6 genotype was associated with no difference in the observed impact on all-cause mortality and the trial combined cardiovascular endpoint," Batty et al. reported.

Based on this, the study investigators concluded that while the CYP2D6*4 variant modulates metoprolol pharmacokinetics and pharmacodynamics, the variant does not adversely impact treatment efficacy. "These results support an individualized dose-titration regimen; guided by patient tolerability and heart rate response," the researchers wrote in their abstract. "The therapeutic target should remain once-daily 200 mg metoprolol CR/XL, or highest tolerated dose."

Association between Adrenergic Receptor Genotypes and Beta-Blocker Treatment Response in Heart Failure Patients: Analysis by Cardiac 123I-MIBG Scintigraphy

Claudio Tinoco Mesquita and several other researchers from the Fluminense Federal University in Brazil investigated cardiac adrenergic activation by the imaging method I123-MIBG scintigraphy before and after heart failure in patients with the Ser49Gly polymorphism of beta-1 adrenergic receptor who received treatment with the non-selective beta-blocker carvedilol.

Previous studies suggest that systolic heart failure patients harboring the Ser49Gly variant have better five-year survival and reduced mortality with beta-blocker treatment than those without this variant. However, the exact influence of this variant is not fully understood in heart failure.

Mesquita et al. recruited 28 patients from the university's heart failure clinic between July 2006 and March 2008. Participants had to have heart failure, be between 30 and 80 years old, have left ventricular ejection fraction of less than 45 percent, and be beta-blocker treatment naive. These subjects were then evaluated by myocardial scintigraphy and genotypic evaluation. The patients were reevaluated via scintigraphy at three-month follow-up.

The study population was 64 percent male, had a mean age of 57.5 years, and mean LVEV of 28 percent. Genotyping showed that 12 patients were homozygous for Ser49Ser and 16 had the Gly49 variant. "The group with Gly49A variant showed, on MIBG washout rate, a significantly higher reduction after three months carvedilol treatment compared to the homozygous group," Mesquita et al. reported in their abstract. "There were no differences in early and late heart/mediastinum ratios between groups."

Based on this data, the researchers concluded that the Ser49Gly B1-adrenoreceptor polymorphism was linked to a better "autonomic response" to carvedilol. "Cardiac innervation as assessed by MIBG scintigraphy can detect distinct response profile to beta-blocker therapy," the authors noted.

Variability in Response: Patterns in Prescribing Antiplatelet Therapy after CYP2C19 Genotyping among Patients with ACS and PCI

Researchers led by Nihar Desai of Brigham and Women's Hospital's Division of Pharmacoepidemiology and Pharmacoeconomics used data from a national claims database to identify, between Jan. 1, 2010, and April 1, 2012, more than 6,000 patients who had recently been prescribed the anticoagulant clopidogrel after an acute coronary syndrome or after having undergone a percutaneous coronary intervention.

These patients were offered genetic testing through the pharmacy benefit manager CVS Caremark, which had launched a program through which payor clients could offer CYP2C19 testing for ACS or PCI patients. Nearly 500 patients agreed to be tested as part of the study, which was funded with an unrestricted research grant from CVS Caremark. Of those who got tested, 146 patients had at least one loss-of-function CYP2C19 allele that made them unlikely to respond as well as normal metabolizers to clopidogrel. Around 3 percent of tested patients had two reduced function alleles, which made them poor responders to the drug.

The researchers then sent the results to the patients' doctors, indicating whether their patients were carriers or non-carriers of a CYP2C19 allele and whether patients were extensive, intermediate, and poor metabolizers of clopidogrel. However, the study investigators did not provide specific treatment recommendations to physicians.

Nihar et al. tracked what physicians did with this information for three months after testing, and found that doctors were "significantly more likely" to change patients' treatment from clopidogrel to prasugrel or increase the clopidogrel dose for carriers of reduced function alleles overall, as well as for intermediate and poor metabolizers. Although clopidogrel metabolism is reduced in patients harboring certain CYP2C19 mutations, prasugrel response doesn't have this pharmacogenetic variability. Furthermore, studies have shown that poor metabolizers and intermediate metabolizers of clopidogrel can overcome their resistance at higher doses of the drug.

However, "although reduced function allele carriers were significantly more likely than non-carriers to be switched to prasugrel (18 percent versus 2 percent), only 20 percent of poor metabolizers had an escalation in their antiplatelet therapy," Nihar and colleagues reported in their abstract.

"Providers were significantly more likely to alter the antiplatelet regimen in carriers of reduced function CYP2C19 alleles, but only 20 percent of those at highest risk were switched to prasugrel," they concluded. "These prescribing patterns likely reflect the unclear impact and rapidly evolving evidence for clopidogrel pharmacogenomics."