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(Circulation. 2005;112:3391-3399.)
© 2005 American Heart Association, Inc.

Heart Failure

Mortality and Morbidity Remain High Despite Captopril and/or Valsartan Therapy in Elderly Patients With Left Ventricular Systolic Dysfunction, Heart Failure, or Both After Acute Myocardial Infarction

Results From the Valsartan in Acute Myocardial Infarction Trial (VALIANT)

Harvey D. White, DSc, FCSANZ; Philip E.G. Aylward, MD, FCSANZ; Zhen Huang, MS; Anthony J. Dalby, MB; W. Douglas Weaver, MD; Ståle Barvik, MD; José Antonio Marin-Neto, MD, PhD; Jan Murin, MD, PhD; Rolf O. Nordlander, MD; Wiek H. van Gilst, PhD; Faiez Zannad, MD, PhD; John J.V. McMurray, MD; Robert M. Califf, MD; Marc A. Pfeffer, MD, PhD, for the VALIANT Investigators

From the Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand (H.D.W.); Cardiovascular Unit, Flinders Medical Centre, Adelaide, Australia (P.E.G.A.); Duke Clinical Research Institute, Durham, NC (Z.H., R.M.C.); Milpark Hospital, Johannesburg, South Africa (A.J.D.); Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Mich (W.D.W.); Department of Cardiology, Central Hospital, Rogaland, Stavanger, Norway (S.B.); Division of Cardiology, University of São Paulo, São Paulo, Brazil (J.A.M.-N.); First Internal Medicine Department, University Hospital, Bratislava, Slovakia (J.M.); Department of Cardiology, Karolinska Institute, Södersjukhuset, Stockholm, Sweden (R.O.N.); Department of Clinical Pharmacology, University of Groningen, Groningen, the Netherlands (W.H.v.G.); Centre d’Investigation Clinique, INSERM-CHU, Hôpital Jeanne d’Arc, Toul, France (F.Z.); Department of Cardiology, Western Infirmary, Glasgow, UK (J.J.V.M.); and Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass (M.A.P.).

Correspondence to Professor Harvey White, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, Auckland 1030, New Zealand. E-mail HarveyW{at}adhb.govt.nz

Received March 24, 2005; revision received July 31, 2005; accepted August 16, 2005.

	Abstract

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Background— The elderly constitute an increasing proportion of acute myocardial infarction patients and have disproportionately high mortality and morbidity. Those with heart failure or impaired left ventricular left ventricular function after acute myocardial infarction have high complication and mortality rates. Little is known about outcomes with contemporary therapies in these patients.

Methods and Results— The Valsartan in Acute Myocardial Infarction Trial (VALIANT) randomized 14 703 patients with heart failure and/or left ventricular ejection fraction <40% to receive captopril, valsartan, or both. Mortality and a composite end point, including cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest, were compared for the age groups of <65 (n=6988), 65 to 74 (n=4555), 75 to 84 (n=2777), and 85 (n=383) years. With increasing age, 3-year mortality almost quadrupled (13.4%, 26.3%, 36.0%, and 52.1%, respectively), composite end-point events more than doubled (25.2%, 41.0%, 52.3%, and 66.8%), and hospital admissions for heart failure almost tripled (12.0%, 23.1%, 31.3%, and 35.4%). Outcomes did not differ between the 3 study treatments in any age group. Adverse events associated with captopril and valsartan were more common in the elderly and in patients receiving combination therapy. With increasing age, use of aspirin, ß-blockers, and statins declined, and use of digoxin, calcium-channel blockers, and non–potassium-sparing diuretics increased. On 3-year multivariable analysis, each 10-year age increase was associated with a hazard ratio of 1.49 (95% CI, 1.426 to 1.557; P<0.0001) for mortality and an odds ratio of 1.38 (95% CI, 1.31 to 1.46; P<0.0001) for readmission with heart failure.

Conclusions— Outcomes remained poor in elderly patients with heart failure and/or impaired left ventricular systolic function after acute myocardial infarction, although most received ß-blockers and all received an ACE inhibitor and/or an angiotensin receptor blocker. Better therapies and increased use of aspirin, ß-blockers, and statins are needed in this important and increasing patient group.

Key Words: aging • angiotensin-converting enzyme inhibitors • captopril • myocardial infarction • valsartan

	Introduction

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Patients >75 years of age constitute approximately one third of all acute myocardial infarction (AMI) cases and account for more than half of the early mortality rate. They also have disproportionately high rates of heart failure, reinfarction, and stroke. Because elderly patients are often excluded from clinical trials,¹ little information is available concerning the benefits or adverse effects of therapies in this age group.

ACE inhibitors and angiotensin receptor blockers have been shown to benefit elderly patients after AMI. However, few studies have directly compared these therapies in this age group.^2–7 The international Valsartan in Acute Myocardial Infarction Trial (VALIANT) compared the ACE inhibitor captopril with the angiotensin receptor blocker valsartan and combination therapy with both agents. There was no upper age limit, and 3160 trial participants (21.5%) were 75 years of age.

The aim of this prospectively defined analysis was to evaluate the effect of age and the study medications on mortality, readmission for heart failure, stroke, and other morbidities, including adverse events related to study medications in VALIANT.

	Methods

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VALIANT randomized 14 703 patients at a median interval of 4.9 days after AMI to receive captopril, valsartan, or both. Details of the inclusion criteria and primary results have been published previously.⁸ To summarize, patients were eligible if they were 18 years of age and developed clinical or radiological signs of heart failure and/or evidence of depressed left ventricular (LV) systolic function with an ejection fraction of <40% or a reduced echocardiographic wall motion index between 12 hours and 10 days after AMI. The major exclusion criteria were cardiogenic shock and a serum creatinine concentration >2.5 mg/dL. There was no upper age limit. The patients were divided into prespecified age groups of <65, 65 to 74, 75 to 84, and 85 years.

Statistical Analysis
Event rates at 3 years were estimated with the Kaplan-Meier method. The Cox proportional-hazard model was used to assess the effect of age on the time to all-cause mortality, with adjustment for baseline characteristics and randomized treatment assignment. The linearity of the effects of age and other continuous covariates was examined by fitting a restricted cubic spline in the model. Linear transformations were applied to those violated linear assumptions. Drug therapy at 3 years was not included in the multivariable analysis. Logistic regression was used to assess the effect of age on admissions to hospital for congestive heart failure, with adjustment for baseline characteristics and randomized treatment assignment. For categorical data, percentages are reported. Interactions between age and randomized treatments were examined to evaluate whether the randomized treatments had differential effects on outcomes in different age populations. Pearson’s and Mantel-Haenszel’s ² statistics were used to compare any 2 or more groups with respect to the outcomes of interest. For continuous data, means and standard deviations or medians with 25th and 75th percentiles are reported. The Wilcoxon rank-sum or Kruskal-Wallis rank test was used to compare any 2 or more groups. The Jonckheere-Terpstra statistic was used to test ordered differences across different age groups.⁹

	Results

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Table 1 lists the patients’ baseline characteristics. Patients 75 years of age constituted 21.5% of the study population, and 383 patients were 85 years of age. Elderly patients were more likely to be female and to have hypertension, diabetes, renal insufficiency, atrial fibrillation, Killip class III or IV heart failure during the index AMI, or a history of stroke or transient ischemic attack. Elderly patients also had lower body weights, were less likely to have a history of smoking or dyslipidemia, and had a slightly shorter delay between symptom onset and randomization. LV ejection fractions were similar in older and younger patients.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics

The use of concomitant medications in the different age groups is shown immediately before randomization in Table 2 and at 3-year follow-up in Table 3. At randomization, use of aspirin, ß-blockers, and statins was lower in older patients than in younger patients, although use of oral anticoagulants was higher in patients 75 to 84 years of age. At the 3-year follow-up, use of aspirin, ß-blockers, and statins remained low in patients 85 years of age, but use of calcium channel blockers and non–potassium-sparing diuretics had increased markedly.

View this table: [in this window] [in a new window]   TABLE 2. Use of Concomitant Medications Immediately Before Randomization

View this table: [in this window] [in a new window]   TABLE 3. Use of Concomitant Medications at 3 Years

Three-year mortality from all causes increased substantially with age, from 13.4% in patients <65 years of age, doubling to 26.3% in those 65 to 74 years of age, almost tripling to 36.0% in those 75 to 84 years of age, and quadrupling to 52.1% in those 85 years of age (Figure 1). The gradient for cardiovascular mortality was similar. Thirty-six percent of cardiovascular deaths occurred in patients 75 years of age. Noncardiovascular mortality also increased progressively from 1.8% in patients <65 years of age to 4.9% in those 65 to 74 years of age, 7.6% in those 75 to 84 years of age, and 13.7% in those 85 years of age, constituting 13.2%, 17.9%, 21.0%, and 23.6%, respectively, of all deaths across the age groups.

View larger version (12K): [in this window] [in a new window]   Figure 1. Kaplan-Meier estimated 3-year rates of all-cause mortality, cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and composite end point (cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest) by age.

There was a shift in the distribution of sudden death versus other causes of death across the age groups (P<0.0001 for homogeneity of the distribution across age groups), with more younger patients dying of sudden death and more older patients dying of pump failure (Table 4).

View this table: [in this window] [in a new window]   TABLE 4. Causes of Cardiovascular Death*

There was a similar but slightly smaller trend in the composite end point of cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest, which occurred 3 times as frequently in patients 85 years of age as in those 65 years of age (Figure 1) but did not differ between the 3 treatment groups (Figure 2). There were age-related increases in the incidence of any readmission for heart failure (P<0.0001; Figure 1) and multiple readmissions for heart failure (P<0.001; Figure 3). Strokes were 4.8 times as common in patients 85 years of age as in those <65 years of age (P<0.0001; Figure 1). Atrial fibrillation developed during follow-up in 5.2% of patients <65 years of age, 9.8% of those 65 to 74 years of age, 12.1% of those 75 to 84 years of age, and 13.2% of those 85 years of age and occurred either at baseline or during follow-up in 8%, 18.2%, 23.8%, and 27.7%, respectively.

View larger version (14K): [in this window] [in a new window]   Figure 2. Kaplan-Meier estimated 3-year rates of all-cause mortality and composite end point (cardiovascular mortality, readmission for heart failure, reinfarction, stroke and resuscitated cardiac arrest) by age and treatment.

View larger version (21K): [in this window] [in a new window]   Figure 3. Three-year rates of readmission for heart failure by age.

On multivariable analysis at 3 years (including all baseline variables), age was an independent predictor of mortality and heart failure, with each 10-year age increase being associated with a hazard ratio (HR) of 1.49 (95% CI, 1.426 to 1.557; P<0.0001) for mortality and an odds ratio (OR) of 1.38 (95% CI, 1.31 to 1.46; P<0.0001) for readmission with heart failure.

Medication Dosages and Safety
Patients in the different age groups were prescribed similar mean doses of captopril and valsartan (P0.1020). However, older patients were less likely to be receiving the recommended doses at 12 months (P0.0206; Table 5).

View this table: [in this window] [in a new window]   TABLE 5. Doses of Study Medications and Use of Recommended Doses at 12 Months

Table 6 lists adverse events leading to dose reduction of the study medications in the different age groups, and Table 7 lists adverse events leading to discontinuation of the study medication. Hypotension, renal dysfunction, and hyperkalemia were more common in patients receiving valsartan (alone or in combination), and coughing was more common in those receiving captopril (alone or in combination). Angioedema was rare in all age groups, and its incidence did not differ between treatment groups. In all 3 treatment groups, elderly patients were more likely than younger patients to have their study medications stopped because of renal dysfunction (Table 7) or reduced as a result of renal dysfunction or hyperkalemia (Table 6). The incidence of hypotension in elderly patients did not differ between treatment groups. Coughing occurred with similar frequency in younger and older patients.

View this table: [in this window] [in a new window]   TABLE 6. Reasons for Dose Reduction of Study Medications

View this table: [in this window] [in a new window]   TABLE 7. Reasons for Discontinuation of Study Medications

To examine the possibility that the effect of age on mortality might be confounded by the discontinuation of study medication, we performed a multivariable regression analysis of age, other baseline covariates, and study medication. We then added to the model discontinuation of study medication (treated as a time-dependent variable) as a result of hypotension or any other cause. Although discontinuation of study medication was significantly associated with all-cause mortality at 3 years (HR, 2.056; 95% CI, 1.566 to 2.700 for discontinuation as a result of hypotension; HR, 1.533; 95% CI, 1.384 to 1.698 for discontinuation for any other cause), the effect of age on all-cause mortality remained largely unchanged. Overall, age was the most influential factor, with an HR of 1.478 (95% CI, 1.414 to 1.546) for every 10-year increase in age.

	Discussion

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In VALIANT, which enrolled a high-risk group of patients with heart failure or impaired LV systolic function early after AMI, 21.5% of patients were 75 years of age. These patients accounted for 32% of cardiovascular events occurring within 3 years (including cardiovascular death, readmission for heart failure, reinfarction, stroke, or resuscitated cardiac arrest) and had almost double the event rate observed in younger patients. The 3-year all-cause mortality rates were 36.0% in patients 75 to 84 years of age and 52.0% in those 85 years of age, and only 21.1% and 26.3%, respectively, of these deaths were due to noncardiovascular causes. More than half of the patients 75 to 84 years of age and more than two thirds of those 85 years of age suffered at least 1 composite end point event during the 3-year follow-up period. Valsartan was at least as effective as captopril in reducing mortality and other adverse outcomes in all age groups, and combination therapy with both agents added no incremental benefit.

In a meta-analysis of 5 long-term trials in patients with LV dysfunction or heart failure after AMI,³ there was a significant mortality reduction in patients <55 years of age (OR, 0.76; 95% CI, 0.62 to 0.93) and a nonsignificant mortality reduction in patients >75 years of age (OR, 0.95; 95% CI, 0.74 to 0.1.22). However, the CI for the older age group was wide, overlapping that of the younger age group. The effectiveness of ACE inhibitors in reducing the combined incidence of death, readmission for heart failure, and AMI was also similar in both age groups (OR, 0.77; 95% CI, 0.66 to 0.91; and OR, 0.89; 95% CI, 0.69 to 1.13, respectively).

Apart from VALIANT, the only major randomized trial comparing ACE inhibition and angiotensin receptor blockade in AMI patients was the Optimal Trial in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL) trial,⁶ which compared a low dose of losartan (50 mg once daily) with captopril (50 mg 3 times daily) in 5477 patients with heart failure during the acute phase of AMI, an LV ejection fraction of 35%, an LV end-diastolic dimension of >65 mm, new left bundle-branch block, new Q-wave anterior AMI, or reinfarction with existing anterior Q waves. The patients enrolled in OPTIMAAL were lower risk than those enrolled in VALIANT (probably because OPTIMAAL used much broader inclusion criteria) and were less likely to undergo revascularization procedures. In addition, OPTIMAAL used a lower dose of angiotensin receptor blocker than VALIANT did. Although OPTIMAAL reported no statistically significant difference in all-cause mortality between treatments, there was a trend for mortality to be higher with losartan (18% versus 16% with captopril; P=0.07), and cardiovascular mortality was significantly higher with losartan than with captopril (15.3% versus 13.3%; P=0.032). Noninferiority of losartan was not proved. The treatment effect of the study medications on all-cause mortality did not differ between patients <65 years of age (n=2170), 65 to 74 years of age (n=1840), and 75 years of age (n=1467). The treatment effect on cardiovascular mortality in the different age groups was not reported. Discontinuation of the study medication (as a result of coughing, skin rash, taste disturbance, or angioedema) was significantly less common with losartan than with captopril. The adverse event rates in the different age groups were not reported. Overall, it is likely that the losartan dose tested in OPTIMAAL inhibited the renin-angiotensin system to a lesser extent than the captopril dose (50 mg 3 times daily) with which it was compared. Consequently, losartan caused fewer adverse effects but was also less effective than captopril. In other studies, a target dose of 100 mg losartan has shown clinical efficacy.^10,11

Many elderly patients either are not prescribed ACE inhibitors¹² or are prescribed doses that are less than evidence based.¹³ In a study of quality of care in elderly patients (mean age, 78 years) who were readmitted for heart failure,¹³ only 14% received evidence-based doses of ACE inhibitors. However, it is not known what ACE inhibitor doses are optimal in the elderly because this age group has been underrepresented in large clinical trials of these agents. In VALIANT, elderly patients had good compliance with the study medications but received lower doses of captopril, valsartan, and combination therapy than younger patients did. In the doses used, captopril and valsartan achieved similar outcomes in elderly patients.

In VALIANT, first and multiple readmissions for heart failure were much more common in elderly patients than in younger patients, although both age groups had similar LV ejection fractions. Age has been shown to be a powerful predictor of admission for chronic heart failure,^14,15 and other influences include the ejection fraction; compliance with medication; diet; and behavioral, social, and psychological factors.^16,17 Use of nonsteroidal antiinflammatory medications, which are commonly prescribed for elderly patients, may also contribute to heart failure requiring admission.¹⁸ In VALIANT, elderly patients were more likely than younger patients to develop new atrial fibrillation, which can result from development or progression of heart failure and can exacerbate heart failure symptoms or trigger embolic stroke. It is also possible that the higher readmission rate in elderly patients was due to a higher incidence of diastolic dysfunction and diastolic heart failure¹⁹; unfortunately, no data on diastolic function were collected in VALIANT. In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM-Preserved) trial,²⁰ candesartan was compared with a placebo and was found to reduce hospital admissions for heart failure in patients with chronic heart failure and preserved systolic function. In VALIANT, the rates of readmission for heart failure in elderly patients did not differ between the captopril, valsartan, and combination treatment groups.

Previous studies have shown that elderly patients are more likely than younger patients to experience adverse events²¹ (particularly renal dysfunction)²² with ACE inhibitors. However, in an analysis of patients with a mean age of 84 years,²³ first-dose hypotension was rare with ACE inhibitors. Studies evaluating the pharmacokinetics of angiotensin receptor blockers in elderly patients have found that plasma clearance is slightly decreased and the elimination half-life is slightly prolonged^24,25; thus, dose adjustment is unnecessary in elderly patients.

Although older and younger patients in VALIANT were randomized to receive similar doses of the study medications, the elderly were more prone to adverse effects of hypotension, renal dysfunction, and hyperkalemia. Hypotension and renal dysfunction were more common with valsartan than with captopril, whereas coughing, skin rash, and taste disturbance were more common with captopril. The incidence of angioedema was similar in the 3 treatment groups. Combination therapy with captopril and valsartan increased the incidence of adverse effects leading to drug discontinuation in all age groups, without improving clinical outcomes. For this reason, we strongly recommend that elderly patients not receive combination therapy with ACE inhibition and angiotensin receptor blockade early after AMI and that elderly patients taking either class of agent receive frequent follow-up with repeated measurement of electrolytes and renal function.

Various other therapies have been shown to be beneficial in patients with heart failure or LV systolic dysfunction after AMI. In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) trial,²⁶ the aldosterone antagonist eplerenone reduced the relative risk of death by 15% over 16 months compared with a placebo in patients randomized 3 to 14 days after AMI with an ejection fraction of 40% and evidence of heart failure (or diabetes mellitus). Background therapy included ACE inhibitors in 87% of patients and a ß-blocker in 75%. VALIANT did not specifically record data on the use of aldosterone antagonists. At baseline, the use of potassium-sparing diuretics was higher in elderly patients than in younger patients, but by the 3-year follow-up, the use was similar in both age groups, having declined in older patients and risen in younger patients.

ß-Blockers have been shown to reduce mortality after AMI in patients with ejection fractions 40%. In the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial,²⁷ carvedilol reduced mortality by 23% during an average follow-up period of 1.3 years. In VALIANT, ß-blockers were used in 76.3% of patients <65 years of age and in 61.6% of those >85 years of age at baseline. At 3 years, the usage rates in these age groups were 77.1% and 52.9%, respectively. At least part of the substantial excesses of mortality and morbidity observed in elderly patients may have been related to lower use of these evidence-based therapies. The use of aspirin and statins was also much lower in elderly patients than in younger patients. There may be a number of reasons for this difference, including patient preference and the occurrence of adverse effects. However, there does seem to be scope for a substantial increase in the low use of aspirin (70.6%), statins (47.1%), and ß-blockers (52.9%) in patients 85 years of age. It is notable, however, that in this age group the use of aspirin and ß-blockers was higher at randomization into VALIANT (86.2% and 61.6%, respectively) than at discharge in Medicare patients hospitalized for AMI (71% and 43.8%, respectively) in 1994 to 1996.²⁸

Some therapies prescribed for elderly patients in VALIANT are known to be potentially harmful. Elderly patients were more likely than younger patients to be taking calcium channel blockers, which have been shown to increase mortality in patients with pulmonary congestion or low ejection fractions (similar to the VALIANT population).²⁹ Usage of non–potassium-sparing diuretics was also higher in the elderly. Although this may have been due to the higher risk status of this age group, these agents have previously been associated with increased mortality and hospitalization for progressive heart failure compared with potassium-sparing diuretics.³⁰

In elderly patients with heart failure or LV dysfunction after AMI, outcomes remained poor despite the high background use of ß-blockers and randomized use of ACE inhibitors and/or angiotensin receptor blockers in all patients. However, the use of other evidence-based therapies was lower in elderly patients than in younger patients. Outcomes were similar with captopril and valsartan, and combination therapy with both agents caused more adverse events without offering advantages. Greater use of evidence-based therapies and better new therapies are needed to improve survival and to reduce the risk of stroke and other comorbidities in this important and increasing patient group.

	Acknowledgments

 
We thank the VALIANT trial participants, Steering Committee, Data and Safety Monitoring Board, Adverse Events Committee, and the many investigators and nurses worldwide who worked on the trial. We are also grateful to Barbara Semb and Charlene Nell for secretarial assistance and to Anna Breckon, ELS, for editorial assistance.

Disclosure

VALIANT was funded by Novartis Pharmaceutical Corp (East Hanover, NJ). Dr White has received research funding and speaking honoraria from Novartis. Dr Aylward has received research funding, other research support, and speaking honoraria from Novartis. Dr Dalby has received a speaking honorarium from Novartis. Drs Weaver, Marin-Neto, and Murin have received research funding from Novartis. Dr Zannad has received research funding from Bayer; speaking honoraria from Pfizer, Sankyo, Guidant, Takeda, and Servier; and consultancy fees from Servier and Guidant. Dr McMurray has received research funding, other research support, speaking honoraria, and consultancy fees from Novartis. Dr Califf has received research funding from Novartis. Dr Pfeffer has received research funding from Amgen, Atherogenics, Bristol-Myers Squibb, Novartis, and Sanofi-Synthelabo; speaking honoraria from Abbott, Amgen, Bristol-Myers Squibb, Novartis, and Pfizer; and consultancy fees from Amgen, Astra Zeneca, Bristol-Myers Squibb, CSL, Genzyme, Guidant, Mitsubishi, and Sankyo. Dr Pfeffer is listed as a coinventor on a patent awarded to the Brigham and Women’s Hospital relating to the use of inhibitors of the renin-angiotensin system in selected survivors of myocardial infarction; there is a licensing agreement between Novartis and the Brigham and Women’s Hospital, which is not linked to sales.

	Footnotes

 
Guest Editor for this article was Raymond J. Gibbons, MD.

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