High-risk Coronary Heart Disease Patients Research Articles

The prognostic value of neutrophil-to-lymphocyte ratio across all stages of coronary artery disease.

The natural history of coronary heart disease (CAD) commonly begins with atherosclerosis, progressing to chronic coronary syndrome (CCS), acute coronary syndrome (ACS), and eventually, heart failure. Despite advancements in preventive and therapeutic strategies, there is room for further cardiovascular risk reduction. Recently, inflammation has emerged as a potential therapeutic target. The neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker which predicts poor prognosis in several conditions such as metabolic syndrome, sepsis, malignancy and CAD. In atherosclerosis, a high NLR predicts plaque vulnerability and severe stenosis. This is consistent with observations in CCS, where an elevated NLR predicts long-term major adverse cardiac events (MACEs). In ACS patients, high NLR levels are associated with larger infarct sizes and poor long-term outcomes. Possible reasons for this include failure of fibrinolysis, ischemia-reperfusion injury and in-stent restenosis, all of which are associated with raised NLR levels. Following myocardial infarction, an elevated NLR correlates with pathological cardiac remodeling which propagates chronic heart failure. Finally, in heart failure patients, an elevated NLR predicts long-term MACEs, mortality, and poor left ventricular assist device and transplant outcomes. Further studies must evaluate whether the addition of NLR to current risk-stratification models can better identify high-risk CAD patients.

Ceramides and Ceramide Scores: Clinical Applications for Cardiometabolic Risk Stratification.

Ceramides are bioactive lipids that have an important role in many cellular functions such as apoptosis and inflammation. During the past decade emerging clinical data have shown that ceramides are not only of great biochemical interest but may also have diagnostic utility. Ceramides have shown independent predictive value for negative cardiovascular outcomes as well as for the onset of type 2 diabetes. Based on abundant published data, risk score using the concentrations of circulating ceramides have been developed and adapted for routine clinical practice. Currently serum ceramides are used clinically as efficient risk stratifiers for primary and secondary prevention of atherosclerotic cardiovascular disease (CVD). A direct cause-effect relationship between CVD and ceramide has not been established to date. As ceramide-specific medications are being developed, conventional strategies such as lipid lowering agents and lifestyle interventions can be used to reduce overall risk. Ceramides can identify a very high-risk coronary heart disease category of patients in need for more intense medical attention, specifically those patients at higher risk as highlighted in the 2019 European Society of Cardiology guidelines for stable chronic coronary syndrome patients. In addition, the ceramide risk score may be used as a decision-making tool in primary prevention patients with moderate CVD risk. Finally, the ceramide risk score may have a unique utility as a motivational tool to increase patient's adherence to medical therapy and lifestyle changes.

Prediction of the risk of mortality using risk score in patients with coronary heart disease.

BackgroundThe aim of the study is to develop risk scores with traditional factors for all-cause and cardiovascular mortality among coronary heart disease (CHD) patients.Methods and ResultsWe performed a prospective cohort study of 1911 CHD patients aged 40 and older. Cox models were used to estimate the association of traditional factors [sex, age, fasting blood glucose (FBG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), blood pressure (BP), and cigarette use] and risk scores with all-cause and cardiovascular mortality. During a mean follow-up of 4.9 years, 232 deaths were identified, 159 of which were cardiovascular-related. Both 4-year and whole follow-up data showed age, sex, HDL-C, LDL-C, and FBG were significantly associated with the risk of mortality, while BP and smoking were not significant predictors in all models. We incorporated age, sex, FBG, HDL-C, and LDL-C to establish risk scores for all-cause and cardiovascular mortality in the 4-year and whole follow-up study. These risk scores were positively associated with the risk of death as quartiles and continuous variables. Assessed by the area under the receiver operating characteristic curves (AUROCs), these risk scores demonstrated strong discriminatory capacity, from 0.744 to 0.763; and the utility of these scores was confirmed with AUROCs from 0.736 to 0.756 (all P<0.001) in a validation cohort of 1506 CHD patients with a mean follow-up of 4.7 years.ConclusionsThese simple risk score assessments, including a set of traditional risk factors, might improve the identification of high-risk CHD patients for a more intensive secondary prevention treatment.

0191: Poor achievement of low-density lipoprotein cholesterol targets in French patients with stable coronary heart disease. Contemporary data from DYSIS II CHD study

We sought to determine achievement of lipid targets according to current European guidelines (low-density lipoprotein cholesterol [LDL-C] ≤70mg/dL) in patients with stable coronary heart disease (CHD) with or without lipid-lowering therapy (LLT), in the French cohort of the Dyslipidemia International Study II CHD (DYSIS II CHD ). DYSIS II CHD was a multicentre observational cross-sectional study conducted from July 2013 to October 2014 in 27 centres in France. Adults with stable CHD (defined as ≥1 of the following: >50% stenosis on coronary angiography or computed tomography, prior percutaneous coronary intervention, prior coronary bypass graft, history of ACS >3 months previously) and a fasting lipid profile done within the previous 12 months were consecutively enrolled. Eligible patients had to be on LLT for ≥3 months or taking no LLT. A total of 436 CHD patients were enrolled. Of the 424 patients (97.2%) on LLT, 91.5% were on statin treatment at the moment of inclusion (mean±SD dose calculated in atorvastatin 27±23mg/day). Non-statin LLT was used in 17.7% patients (79.2% were on a cholesterol-absorption inhibitor). Mean±SD LDL-C was 87.4±30.5mg/dL, 28.4% achieved LDL-C<70mg/dL, and 67.7% had an LDL-C<100mg/dL (Table). Abstract 0191 – Table: Characteristics of lipid values in patients with stable CHD All patients (n=436) LLT (n=424) No LLT (n=12) Age (years) 69±12 69±12 74±12 Men 80.0 79.7 91.7 ACS >3 months previously 70.0 70.0 66.7 Diabetes type 2 27.0 27.3 16.7 Chronic kidney disease 5.0 5.2 0 Lipid variables LDL-C (mg/dL) 87.4±30.5 86.0±29.6 135.3±24.5 ** LDL <70 mg/dL 28.4 29.2 0 * Distance to target of <70 mg/dL (mg/dL) 31.1±24.2 29.7±23.2 65.3±24.5 ** LDL <100 mg/dL 67.7 69.3 8.3 ** Data are mean±SD or %. * P<0.05 ** P?0.0001 (LLT vs no LLT) These observational data from contemporary clinical practice in France indicate suboptimal lipid control, with over two-thirds of high-risk CHD patients failing to achieve the LDL-C target despite taking LLT, and a large difference between mean value and target LDL-C. More-intensive treatment is required to optimize achievement of lipid goals in CHD.

Association between cholesterol synthesis/absorption markers and effects of cholesterol lowering by atorvastatin among patients with high risk of coronary heart disease

No indices are currently available to facilitate clinicians to identify patients who need either statin monotherapy or statin-ezetimibe combined treatment. We aimed to investigate whether cholesterol synthesis and absorption markers can predict the cholesterol-lowering response to statin. Total 306 statin-naïve patients with high risk of coronary heart disease (CHD) were treated with atorvastatin 20 mg/day for 1 month. Cholesterol synthesis and absorption markers and LDL cholesterol (LDL-C) levels were measured before and after treatment. Atorvastatin decreased LDL-C by 36.8% (range: decrease of 74.5% to increase of 31.9%). Baseline cholesterol synthesis marker lathosterol and cholesterol absorption marker campesterol codetermined the effect of atorvastatin treatment. The effect of cholesterol lowering by atorvastatin was significantly associated with baseline lathosterol levels but modified bidirectionally by baseline campesterol levels. In patients with the highest baseline campesterol levels, atorvastatin treatment decreased cholesterol absorption by 46.1%, which enhanced the effect of LDL-C lowering. Atorvastatin treatment increased cholesterol absorption by 52.3% in those with the lowest baseline campesterol levels, which attenuated the effect of LDL-C reduction. Especially those with the highest lathosterol but the lowest campesterol levels at baseline had significantly less LDL-C reduction than those with the same baseline lathosterol levels but the highest campesterol levels (27.3% versus 42.4%, P = 0.002). These results suggest that combined patterns of cholesterol synthesis/absorption markers, rather than each single marker, are potential predictors of the LDL-C-lowering effects of atorvastatin in high-risk CHD patients.

GW24-e1865 Association between cholesterol synthesis/absorption markers and effects of cholesterol lowering by atorvastatin among patients with high risk of coronary heart disease

ObjectivesNo indices are available to facilitate clinicians to identify patients who need either statin monotherapy or statin-ezetimibe combined treatment. We aimed to test whether cholesterol synthesis and absorption markers can...

Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy

BackgroundMany high-risk coronary heart disease (CHD) patients on statin monotherapy do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals, and combination lipid-lowering therapy may be considered for these individuals. The effect of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin therapy versus titrating these statins on LDL-C changes and goal attainment in CHD or CHD risk-equivalent patients was assessed in a large, managed-care database in the US.MethodsEligible patients (n = 17,830), initially on statin monotherapy who were ≥18 years with baseline and follow-up LDL-C values, no concomitant use of other lipid-lowering therapy, and on lipid-lowering therapy for ≥42 days, were identified between November 1, 2002 and September 30, 2009. The percent change from baseline in LDL-C levels and the odds ratios for attainment of LDL-C <1.8 and <2.6 mmol/L (70 and 100 mg/dL) were estimated using an analysis of covariance and logistic regression, respectively, adjusted for various baseline factors.ResultsLDL-C reductions from baseline and goal attainment improved substantially in patients treated with ezetimibe added onto simvastatin, atorvastatin, or rosuvastatin therapy (n = 2,312) versus those (n = 13,053) who titrated these statins. In multivariable models, percent change from baseline in LDL-C was −13.1% to −14.8% greater for those who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin versus those who titrated. The odds of attaining LDL-C <1.8 and <2.6 mmol/L (70 and 100 mg/dL) increased by 2.6–3.2-fold and 2.5–3.1-fold, respectively, in patients who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin versus titrating statins.ConclusionCHD/CHD risk-equivalent patients in a large US managed-care database, who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin, had greater LDL-C reductions and goal attainment than those who uptitrated these statin therapies. Our study suggests that high-risk CHD patients in need of more intensive LDL-C lowering therapy may benefit by adding ezetimibe onto statin therapy.

Complementary/Alternative Medicine in Cardiovascular Diseases 2013

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and the mortality is likely to further accelerate in many developing countries. In 2008, almost one in three deaths all over the world was attributed to CVDs. It is also estimated that by 2030 over 23 million deaths from CVDs will occur each year. Despite advances in modern management of CVDs, either revascularization or medical therapy, complications related to these procedures and recurrent acute cardiovascular events still afflict patients. Meanwhile, patients with CVDs often suffer from unfavorable quality of life. In recent decades, the potential benefit of complementary/alternative medicine (CAM) therapy in improving CVDs prognosis has drawn more and more attention, and the use of CAM by physicians and patients has also increased markedly. However, the evidence of CAM for CVDs patients and the research on mechanism of actions are still insufficient. Last year, the published special issue named “The potential benefit of complementary/alternative medicine in cardiovascular diseases” got a great success, which facilitates the compilation of this special issue 2013. We believe that such a series can have a long-term impact, and in time gather a community around it in much the same way a successful annual conference does. In this issue, original research papers and reviews from different parts of the world including China, Republic of Korea, USA, Germany, and Malaysia are presented. These papers are focused on the mechanism of action and the clinical application of CAM in treating CVDs. In the clinical trials, the benefits of Chinese medicine and some other CAM therapies for CVDs patients were demonstrated. A multicenter prospective cohort study showed that heart failure, age ≥65 years old, and myocardial infarction were associated with an increase in one-year follow-up incidence of major adverse cardiac events (MACEs) in hospitalized coronary heart disease patients, and integrative medicine showed a tendency for reducing the incidence of MACEs. The similar benefit of integrative medicine therapy for patients with acute coronary syndrome after PCI was showed in a multicenter randomized controlled trial (RCT), 5C trial. Another RCT compared the effectiveness of Qi-shen-yi-qi dripping pills (QSYQ) with that of aspirin in the secondary prevention of myocardial infarction. This trial did not show significant difference of primary and secondary outcomes between aspirin and QSYQ, which suggest QSYQ might be an alternative medication for patients' intolerance of aspirin in patients who have had an MI. Specifically, a new potential biomarker of “toxin syndrome” in coronary heart disease patients was proposed in a paper containing two clinical trials. The authors concluded that the new biomarker “inter-alpha-trypsin inhibitor heavy chain H4” might have a potential role in early identifying high-risk coronary heart disease patients in stable period. Most of the experiment researches in this issue were focused on Chinese medicine and Korean medicine. Two researches explored the role and mechanism of Qiliqiangxin capsule (QL), an oral Chinese proprietary medicine, for arrhythmia and heart failure, respectively. A pharmacological research showed that blocking androgen receptor could abolish the ability of Panax ginseng to protect the heart from myocardial ischemia reperfusion injury. The benefit of Doinseunggitang, a Korean traditional prescription, on the treatment and prevention of diabetic vascular complications was also described in a study. A systematic review suggested that oral Panax notoginseng preparation could relieve angina pectoris related symptoms. Meanwhile, the potential benefit of Qiju Dihuang Wan, a Chinese herbal prescription, on the treatment of essential hypertension was also reviewed. Additionally, yoga was recommended as an effective intervention for reducing blood pressure in a systematic review. Due to indefinite mechanism of actions and lacking of high quality evidence, traditional Chinese medicine and other traditional medicine worldwide are considered as CAM in Western countries. In this case, original researches on mechanism of actions play an important role in the modernization and internationalization of CAM and should be further strengthened in future researches. In the hierarchy of evidence-based medicine, high quality RCT is still considered as the golden standard for evaluating interventional treatment. Currently, multicenter RCTs and a prospective cohort study have been conducted to evaluate the benefit of CAM for CVDs, and most of these researches showed positive findings. Nevertheless, the effectiveness of CAM on the treatment of CVDs in the real world is still unclear which limits the application of CAM. The reason is that efficacy of intervention in RCT is not equal to its effectiveness in the real world. In the future, in addition to high quality RCTs, more evidence from real world researches is warranted to support the use of CAM including traditional Chinese medicine for CVDs patients. Ke-ji Chen Ka Kit Hui Myeong Soo Lee Hao Xu

Adherence of hospital-based cardiologists to lipid guidelines in patients at high risk for cardiovascular events (2L registry)

According to various national and international guidelines, the target LDL-C level is <100mg/dl for patients with established coronary heart disease (CHD) or CHD risk equivalent (CE). We aimed to investigate aspects of the lipid-lowering management of patients at high cardiovascular risk in-hospital care and the achievement of target values. In the internet-based 2L registry in Germany (2005-2006), cardiologists in 42 hospitals documented at a single visit 3,131 consecutive patients with known CHD, and/or diabetes mellitus, peripheral arterial disease, or a 10-year CHD risk >20% (summarized as CE), who were on chronic statin treatment. They received instructions on the guidelines and instant feedback on the effect of their treatment decisions (educational study component). The three groups comprised 1,458 patients with CHD+CE (46.6%; median LDL-C 107mg/dl), 1,104 patients with CHD only (35.3%; median LDL-C 104mg/dl), and 569 with CE only (18.2%; median LDL-C 111mg/dl). At admission, LDL-C levels <100mg/dl were observed in 43.1, 44.8 and 37.9% of patients in the three groups, respectively. Statin doses at admission were usually in the low to intermediate range (e.g., simvastatin 10-20mg/day). Cardiologists switched to another statin in 14.6%, increased the dose of statins (if same drug) in 22.9% (mean increase from 26.8mg/day at baseline to 31.6mg/day) and/or added a cholesterol absorption inhibitor (CAI) in 11.6%. The cardiologists' intervention improved estimated LDL-C levels (using a lipid calculator); however, the 100mg/dl LDL-C target was only reached in 49.0, 48.5, and 42.9%. When compared with earlier studies in the outpatient setting, the treatment to target for LDL-C of high-risk CHD patients has improved, but is not satisfactory.

Ezetimibe/simvastatin 10/20 mg versus simvastatin 40 mg in coronary heart disease patients

Reducing low-density lipoprotein cholesterol (LDL-C) is the primary goal of therapy in patients with hypercholesterolemia and coronary heart disease (CHD). This double blind placebo-controlled study enrolled patients 18 to 75 years of age with primary hypercholesterolemia and established CHD who were taking a stable daily dose of simvastatin 20 mg. Patients were randomized to ezetimibe/simvastatin 10/20 mg (eze/simva; n = 56) or simvastatin 40 mg (simva; n = 56) for 6 weeks. Percent change from baseline in LDL-C, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides were assessed by use of the Student t test. The percent of patients achieving LDL-C less than 100 mg/dL (<2.6 mmol/L) or less than 80 mg/dL (<2.0 mmol/L) was analyzed via logistic regression with terms for treatment, baseline LDL-C, age, and gender. Baseline characteristics were similar between groups. Treatment with eze/simva combination resulted in significantly greater reductions in LDL-C, total cholesterol, and triglycerides versus doubling the dose of simva to 40 mg (all P < .01). Significantly more patients achieved LDL-C less than 100 mg/dL (<2.6 mmol/L) and less than 80 mg/dL (<2.0 mmol/L) with ezetimibe/simvastatin versus doubling the dose of simva to 40 mg (73.2% vs 25.0%; P < .001) for simvastatin. Changes in HDL-C were similar between treatments. Both treatments were generally well tolerated. In high-risk CHD patients with hypercholesterolemia, treatment with eze/simva combination resulted in significantly greater reductions in LDL-C, total cholesterol and triglycerides, as well as greater achievement of recommended LDL-C targets, compared with doubling the simvastatin dose to 40 mg over the 6-week period. ( NCT00423579).

Identification of High-Risk Coronary Heart Disease Patients Receiving Atypical Antipsychotics

Although psychiatric patients have a shortened life expectancy due to increased coronary heart disease (CHD), early identification of high-risk patients and targeted prevention for reduction of low-density lipoprotein (LDL) cholesterol are suboptimal in clinical care. We aimed to compare the accuracy of a single LDL-cholesterol intervention threshold of > 130 mg/dL (recently proposed for psychiatric patients) with that of the more complex LDL-cholesterol targets defined by the National Cholesterol Education Panel (NCEP). The study was performed in patients receiving second-generation antipsychotics (SGAs), a medication class associated with CHD risk. Three hundred fifty-six psychiatric patients receiving SGAs underwent standard LDL-cholesterol target assessments upon admission to the hospital between August 1, 2004, and March 1, 2005. The expert consensus-recommended > 130-mg/dL LDL-cholesterol threshold was used to determine false-negative results among patients with above-target NCEP-defined LDL cholesterol and false-positive results in the group with below-target NCEP-defined LDL cholesterol. The > 130-mg/dL threshold misclassified 15 (14.9%) of 101 high-risk patients and 31 (12.2%) of 255 low-risk patients (mean +/- SD 10-year CHD risk: 23.1% +/- 12.2% and 2.1% +/- 2.2%, respectively). Results were similar in the 171 schizophrenia patients. Misclassified patients with above-target LDL cholesterol were more likely than correctly identified patients to have diabetes (p = .0002), greater 10-year CHD risk (p = .0006), higher age (p = .0008), metabolic syndrome (p = .0018), and past CHD events (p = .0025). No distinguishing factors for false-positive cases could be identified. The > 130-mg/dL LDL-cholesterol intervention threshold operated poorly in our psychiatric population. To avoid substandard care, NCEP-defined LDL-cholesterol targets should be used for the routine detection of psychiatric patients treated with antipsychotics who require interventions to decrease CHD risk.

Reduced Mortality Rates after Intensive Statin Therapy in Managed-Care Patients

Objectives To evaluate whether intensive statin therapy in a managed-care setting produces greater clinical benefit than more moderate statin use. Methods Adults hospitalized for a coronary heart disease (CHD) event were identified from a longitudinal database of pharmaceutical and medical claims. Propensity scores representing a patient's likelihood of receiving statin therapy were calculated. Statin-treated patients were those who received statin therapy within 30 days of hospital discharge after a CHD event, had been supplied with statin therapy for at least 10 days during the follow-up period, and received statin therapy for at least 10 days before the first recurrent CHD event. Standard or intensive statin therapy was identified according to low-density lipoprotein cholesterol reductions expected with statin dose. Patients in the standard and intensive groups were matched by propensity scores to patients not receiving statin therapy after discharge. Patients in the standard statin therapy group were also matched to patients who received intensive statin therapy. Mortality rates after hospital discharge were compared in all matched groups. Results Patients treated with standard therapy experienced a 32% reduction in risk of death compared with patients not receiving statin therapy ( P = 0.003). Patients who received intensive statin therapy after a CHD event experienced a 42% reduction in risk of mortality ( P = 0.002) versus those not receiving statin therapy. Compared with standard therapy, intensive statin treatment further reduced the risk of death by 29% ( P = 0.020). Conclusion High risk CHD patients benefit from intensive statin therapy in a real-world, managed-care cohort, confirming the results of randomized clinical trials.

Under treatment with lipid-lowering drugs of high-risk coronary heart disease patients of the GENICA study.

To assess the proportion of high-risk coronary artery disease (CAD) patients who received lipid lowering drug treatment (LLDT) and met the LDL-Cholesterol (LDL-C) goal of 100 mg/dl defined by the third report of the U.S. National Cholesterol Education Program (NCEP). In 86% (n = 1095) of the 1268 consecutive Italian patients, who were enrolled in the GENICA study after undergoing quantitative coronary angiography for suspected coronary artery disease between 1999 and 2001, the levels of total serum cholesterol, HDL-cholesterol, triglycerides, and LDL-C were measured and accurate information on current LLDT were available. All patients were classified according to the NCEP. Seventy-four percent of the patients (n = 805) had established CAD and cardiovascular events and therefore were candidates for secondary prevention with LLDT; 69% of them had concomitant hyperlipidemia. Only 57% of the patients with CAD and hyperlipidemia were on LLDT. Of the 1052 patients who were at the highest risk class according to NCEP, only 34.2% and 16.7% were on LLDT and reached the LDL-C goal, respectively. Only 1 patient of 6 in the highest-risk class according to the NCEP accomplished the LDL-C goal. Accordingly, in the field of secondary prevention of coronary artery disease, the implementation of guidelines that emerged from scientific evidence into clinical practice with LLDT still requires major efforts.

Changes in Sample Size and Length of Follow-up to Maintain Power in The Coronary Artery Bypass Graft (CABG) Patch Trial

The CABG Patch Trial is testing the hypothesis that prophylactic use of implantable cardiac defibrillators (ICDs) will improve survival in high-risk coronary heart disease patients undergoing CABG surgery. The original design called for 800 patients to be randomized to ICD prophylaxis or to no therapy and followed for 2 to 6.5 years (average, 40 months) to a common termination date. Since the ICD pulse generators used in this trial lasted about 42 months, the original design required ICD replacement in many patients. At its first two meetings in 1993, the Data and Safety Monitoring Board (DSMB) formalized a plan to adjust sample size in October 1994 if the control group mortality rate was lower than expected. In June 1994, an unanticipated and unique event—a subpoena from the Office of the Inspector General (OIG)—made it impossible to replace about half of the ICD generators and threatened to shorten follow-up substantially. If follow-up had been stopped on the date originally planned, but without replacing ICDs, the average follow-up would have fallen from 40 months to about 33 months. Also, in October 1994, the control group mortality rate was found to be somewhat lower than expected. Together, the abbreviated follow-up and lower control group mortality threatened to reduce power substantially. The DSMB reviewed several options for restoring power. Because mortality rates in the first month after CABG surgery were about seven times as high as thereafter and because ICD therapy did not reduce surgical mortality (death during the first 30 days), extending the follow-up benefits power more than does increasing the sample size. However, the limit on extending follow-up was 42 months (the expected battery life of the ICD). Data from the ICD-treated group was not reviewed or considered in making the decision. After reviewing many options for restoring power, the DSMB recommended that the sample size be increased from 800 to 900 patients and that almost all patients be followed for 42 months. This recommendation extended follow-up for 2 years beyond the original termination date planned for the trial and dictated that patients close out after 42 months rather than on a common termination date.