The elderly patient with coronary artery disease (CAD) poses unique challenges in clinical management. The basic problem is that there are insufficient data from dedicated clinical trials to provide a framework for decision making. Clinical decisions in elderly patients are thus mainly empiric. The proportion of elderly patients who are included in randomized revascularization trials is much lower than the actual percentage in the CAD population as a whole.1 Elderly patients in registries and large series exhibit the greatest benefit from interventional procedures when compared to patients in the general population, but they also run the highest risk of complications. Consequently, the younger age groups are preferentially revascularized in clinical practice, a paradoxical utilization of resources in a population that derive the least demonstrable benefit.2 Percutaneous coronary intervention (PCI) is less invasive than coronary artery bypass graft surgery (CABG) and requires a shorter recovery time. Such benefits would appear to be particularly advantageous in the elderly, especially those with coexisting noncardiac disorders that may pose significant additional operative risk. Conversely, the limited expected lifespans render conclusions concerning long-term benefits dependent on many extraneous factors besides treatment effect. Despite the fact that over 50% of all PCIs in the United States are performed in patients older than 65, the basic medical tenet to “first do no harm” leads to conflicting philosophical approaches. Further, since clinical trials of new therapies frequently exclude this age group, any conclusion about the efficacy of new techniques are inferential or based on observational data from registries and small series. Additionally, many randomized trials of PCI in various clinical settings have a bias in case selection, either specifically or indirectly excluding elderly patients. This bias may be particularly prominent in some studies that have a defined upper age limit for randomization, but may also be present due to exclusions when certain high-risk factors found in a high percentage of elderly patients are prespecified. Physicians therefore must rely on clinical judgment to choose which elderly patients should undergo invasive procedures, and cannot depend on a complete evidence base to assist in reaching decisions. There are at least six different characteristics the physician should assess in reaching this decision: (1) mental status (i.e., dementia versus mentally active); (2) emotional status (i.e., the patient wants to live as long as possible versus a readiness to die); (3) independence (i.e., the patient lives alone versus being incompetent); (4) physical activity (i.e., immobile or bedridden versus a vigorous lifestyle); (5) compliance with medications; and (6) comprehension, by both patient and family, of the potential benefits and risks of a revascularization procedure. The elderly are best considered as being comprised of several different subpopulations with differing therapeutic goals. Patients who are between the ages of 65 and 70 years can be considered the “young old”; that is, very active young retirees or individuals who are near the end of their working careers. These people travel widely and are relatively healthy. The second group includes those between the ages of 70 and 80 years; this group can be considered the “retired old.” These patients become increasingly less independent, but for the most part, enjoy their retirement. Finally, there are the octogenarians, or the “old old.” Many of these patients live in nursing homes or other assisted living arrangements. These distinctions are important because the expectations of people in each of these age categories in regard to their medical care differs both in terms of life expectancy and quality of life. Further, the elderly have limited access to medical care in our society.3,4 This is evident in numerous ways: (1) they have limited access to transportation to bring them in a timely fashion to the doctor’s office or emergency room; (2) their insurance coverage is limited in many cases; and (3) the medical system generally is less aggressive in the treatment of frail, elderly patients. Short- and Long-Term Outcomes after PCI The contemporary in-hospital mortality rate of PCI is generally low in all age groups, but continues to be higher in patients over the age of 65. Age is powerfully associated with worse short-term prognosis and a greater rate of PCI-related complications.3–5 The expected in-hospital mortality rate is less than 0.5% for patients less than 65 years of age, but ranges from 2.2–4.0% for patients older than 75 years. The total complication rate for elderly patients is 9%, compared to 6% for that of younger patients. Postprocedural renal failure and bleeding are more common in elderly patients undergoing PCI than in younger patients.5,6 On the other hand, the overall long-term survival after successful PCI is good, even for the very elderly. Restenosis occurred in 15–30% of successful PCI cases prior to the arrival of drug-eluting stents and was not more common in the elderly. Excellent long-term relief of symptoms is achieved in most elderly patients who present with angina pectoris. However, patients over age 75 who undergo PCI appear to have a higher recurrence rate of symptoms than do younger patients, even with stent implantation.7 One possible reason for this higher rate of recurrence is that these patients are less likely to have complete revascularization than younger patients. Additionally, the more extensive disease likely represents more potential areas of progression and vulnerable plaques.8 Whether the use of drug-eluting stents has altered these long-standing observations has not yet been systematically evaluated, but no age-related differences up to age 65 have been identified. Drug-eluting stent trials have had 65 years, preventing a definitive subgroup analysis.24 The Rotterdam group9 has suggested the likelihood of a similar beneficial effect compared to bare metal stents based on one-year outcomes in 46 octogenarians. Data from the e-Cypher registry suggest that drug-eluting stents are probably as effective in the elderly population as in other age groups in preventing restenosis, but this has not been formally tested.19 Weintraub and colleagues10 constructed the generally accepted survival curves after balloon angioplasty based upon age. In every decile of age, survival over the course of the subsequent 2- to 10-year period diminishes. This observation has subsequently been confirmed in numerous other registries, including Medicare,11 the New York State Registry,12 and the Society of Cardiac Angiography and Intervention.13 The majority of studies assessing outcomes in elderly patients undergoing PCI in the balloon PTCA era reported less successful revascularization outcomes and more adverse events than in younger patients.5 Although coronary stents have improved clinical outcomes, registry data continue to demonstrate worse outcomes than in age-matched controls.6–9,14–16 Such observations have led some to question the value of aggressive PCI strategies in elderly patients.11,17 The relative survival rates of PCI versus CABG versus medical therapy in similar patient types from a single, large center or registry have not been definitively assessed in the contemporary stent era. Recently, a randomized trial of invasive versus medical therapy in the elderly found that patients older than 75 years of age benefit more from revascularization than from optimized medical therapy. Both symptom relief and quality of life were enhanced in patients undergoing PCI. However, this is a small trial with only six-month follow up.18 Conversely, Tu et al.20 evaluated the use of cardiac procedures and outcomes in elderly patients in the United States and in Canada. The authors found that U.S. patients were more likely than Canadian patients to undergo coronary angiography (34.9% versus 6.7%; p p = 0.03). However, the one-year mortality rates were virtually identical (34.3% United States versus 34.4% Canada; p = 0.94). The Alberta Provincial Project for Outcome Assessment and Coronary Heart Disease Study21 is a Canadian study demonstrating that elderly patients experience the largest absolute risk reductions associated with CABG or PCI compared to younger patients. Adjusted four-year survival rates in CABG and PCI patients were compared to medical therapy. The data demonstrated that the largest absolute risk reduction associated with revascularization was observed in the oldest patients. Additionally, the elderly also experienced the highest medical- and revascularization-associated mortality rates of any age group. These findings are important in illustrating the benefits of an aggressive revascularization strategy in elderly patients. Seto et al.22 showed that quality of life improvements after PCI are not age-dependent. These authors evaluated the medical outcomes in a study using the Short Form Survey and Seattle Angina Questionnaire in a group of 295 patients over the age of 70 and 1,150 younger patients. At six months, physical health had improved in 51% of elderly patients, and mental health had improved in 29% of patients undergoing PCI. The authors found that the probability of clinically meaningful improvement in lifestyle following PCI was not significantly associated with age; elderly patients are just as likely to experience improved enjoyment in their life as younger patients after PCI. That post-PCI survival, but not quality of life, is age-dependent is a crucial observation, and is an important consideration in patient selection. Physical and mental health improvements are very important to the elderly. Especially as patients get older, it is reasonable that their goal may be to live better rather than longer. Technical Factors The technical feasibility of PCI in the elderly has been well studied. Initial success rates range from 92–99%, and the success rate is high, even for very old patients. In the BARI trial,23 the five-year survival rate with angioplasty was similar to that with bypass surgery although, as found in the total study group, diabetics have a better survival rate when treated with bypass surgery. Mortality and morbidity rates with PCI are highest for the elderly population because the patients are frail and have more advanced disease. Also, in older patients, the occurrence of any procedural complication is associated with subsequent mortality. Specific technical considerations often cited in elderly patients include heavier coronary calcification, tortuous anatomy in both coronary and vascular approaches, and higher cerebral, renal and pulmonary morbidities. The heavier calcification, in general, frequently renders technical aspects of the procedure more difficult and may lead to increased utilization of ablative devices, such as in rotational atherectomy procedures. Renal dysfunction and anemia, often of ill-defined cause, result in reduced tolerance to bleeding complications. Peripheral vascular disease with a tortuous aorto-iliac system and often subclavian vessels may significantly affect access for interventional procedures. Adjunctive anticoagulation in the catheterization laboratory has to be considered separately in the elderly. In REPLACE-2,25 bivalirudin was more efficacious in the > 75-year-old subgroup (2.5% reduction in primary endpoint, 15.2% vs. 12.7%) than in those 65 years was greater compared to those 27 specifically relate to the anticipated outcomes of PCI has not been evaluated in a clinical study, nor has their physiologic significance been evaluated in conjunction with altering technical details of the procedure (e.g., balloon inflation time, contrast load, etc.). Risk Factors Predictive of PCI Outcome — Prevalence in the Elderly Patient Women constitute the majority of patients with CAD in the elderly population, while men predominate in patients with CAD under the age of 65 years. In patients aged 65 years or less, approximately 70–80% are male; between the ages 65 and 70, however the ratio is 50:50; in ages 70 to 80 years, 60% are female; and over the age of 80 years, 70% are female. Since women have smaller coronary vessels commensurate with smaller body size generally, it has been hypothesized that the worse outcomes of PCI in women are related to the mechanical factor of working in a smaller-diameter lumen. Additionally, the restenosis rate is increased both in smaller vessels and in women.15 Finally, it has been well demonstrated that women with CAD have more multivessel CAD and more frequently present with prior MI and decreased left ventricular function than do men.28 Another challenge to the physician is that the elderly have more comorbidities such as diabetes, peripheral vascular disease or stroke. They tend to be more symptomatic and present more often with class III or IV angina. Frequently, there are numerous coexisting clinical factors associated with worse outcomes after PCI. For example, chronic renal insufficiency, prior myocardial infraction, low ejection fraction, and female gender are all risk factors that predominate in the elderly. Another key factor is that the elderly tend to have more multivessel disease than the population under the age of 65. Single-vessel disease usually predominates at younger ages, but after the age of 65, the incidence of multivessel disease increases to 60–65%. Additionally, as the age of patients with CAD increases, the incidence of CHF, prior revascularization, previous MI and renal insufficiency increases substantially.29 With increasing age, the number of in-hospital complications associated with coronary intervention also increases. The incidence of myocardial infarction, unplanned CABG, and in-hospital death is greater in elderly patients. The higher rate of MACE is related to age, and is at least partially independent of other risk factors. All registries from 1999 onward have shown at least partial age-independence of worse outcomes.16 This observation implies a highly complex relationship among age, comorbid factors, and prognosis that will require further investigation. Elderly patients presenting with acute coronary syndromes are more likely to have an atypical presentation and often have a high prevalence of multiple comorbidities that are likely to significantly impact treatment, as well as immediate and late patient outcomes.2,30 Patients over the age of 80 presenting with chest pain are more likely than those in their 70s to have acute myocardial infarction (mostly non-ST-elevation) (35% vs. 9.7%), heart failure (33.3% vs. 19.4%), and renal dysfunction (21.6% vs. 12.3%). They are also less likely to undergo coronary angiography (29.3% vs. 43.8%).31–36 Numerous studies and registries document the increased mortality rates and worse outcomes after bypass surgery in the elderly. The traditional risk factors for CAD (hypertension, diabetes mellitus, total cholesterol/HDL ratio) are less prevalent in those over 80,5,31 and the elderly also have undergone prior revascularization procedures less often. They are less likely to receive interventional or pharmacologic therapy3 and are more likely to present late after symptom-onset in acute myocardial infarction.4,18 Eckart et al.32 reviewed cases from 1994 to 1997 and found a marked increase in short-term mortality in octogenarians undergoing PCI in which outcomes were strongly influenced by risk factors of depressed left ventricular function and chronic renal insufficiency. Voudris et al.37 recently reported the long-term outcome of patients older than 70 years of age, and confirmed a strong relationship between decreased ejection fraction and long-term mortality in the elderly despite contemporary medical therapy. Renal insufficiency also is associated with worse PCI outcomes in general.6,36 The National Cardiovascular Network8 demonstrated the impact of these features when evaluated in a population-based analysis. In the elderly group (average age: 80), 53% were female versus only 31% in those under the age of 80. Sixteen percent had congestive heart failure in the octogenarian group, which was twice that in the younger patient group. There was also a doubling in the incidence of chronic renal insufficiency and cerebral vascular disease. Multivessel disease was more frequent in this age group, occurring in 57% versus 45% in the under-80 age group. Commensurate with age, the risk of death or death/MI/CVA as a combined endpoint increased considerably once past the age of 65 years. Shaw et al.6 analyzed the National Cardiovascular Data Registry to demonstrate that there are numerous factors predictive PCI outcomes. Age is one of the most substantial independent factors; for every ten years of age, the odds ratio of risk was 2.14 and the confidence interval was 0.8–2.6. Klein et al.32 specifically evaluated the outcomes of PCI in octogenarians in this registry. Even within a patient group comprised entirely of patients over the age of 80 years, age remained an independent risk factor for in-hospital mortality after PCI; the odds ratio was 1.03 (95% CI 1.00–1.07) for each additional year of age greater than 80. Additionally, elderly patients who presented with acute myocardial infarction, baseline chronic renal insufficiency, chronic obstructive pulmonary disease, peripheral vascular disease, diminished ejection fraction, or prior coronary intervention had increased risk. The authors produced a simple, clinically useful mathematical model that is strongly predictive of outcomes in octogenarians. Dynina and colleagues38 concluded that older patients should not be categorically denied coronary intervention based on data collected prospectively on almost 11,000 patients undergoing PCI during a 12-month period in five New York City hospitals. They evaluated the in-hospital mortality rates of patients older than 65 years with those of younger patients. Age was an independent predictor of adverse outcomes, but prognosis also was strongly influenced by associated comorbidities. In this study, stents were placed with equal frequency in the very elderly and younger patients: 82% versus 81%, respectively. Procedural success was 96% in the very elderly versus 97% in the younger patients. In-hospital mortality occurred in 2.5% in the very elderly patients versus 0.6% among younger patients. Independent predictors of mortality were myocardial infarction within 6 hours of chest pain onset, hemodynamic instability and congestive heart failure at the time of admission. The economic consequences of restenosis in a contemporary unselected elderly population were studied by Clark et al.39 These authors used the Medicare Standard Analytical File to identify all initial PCI procedures performed in 1998 among a random sample of Medicare beneficiaries greater than 65 years of age. Almost 10,000 patients were followed for one year after PCI. Between one month and one year after PCI, approximately 17% of patients required at least one repeat revascularization procedure. Mean one-year medical costs increased five-fold among such patients. After adjusting for baseline differences, the independent cost of repeat revascularization was approximately $19,000. Thus, in unselected elderly patients undergoing PCI, repeat revascularization occurs in about 17% and increases one-year costs by more than $19,000 per occurrence. Specific Clinical Scenarios The very elderly patient may present with typical chest pain and electrocardiographic changes, but more often than younger patients, the presentation is atypical, with increasing dyspnea, decreasing physical activity, worsening heart failure or confusion.2,30 The incidence of silent MI is also high in the elderly.40 Classic symptoms may be masked by physical inactivity, and extensive CAD may be present at the time of first presentation.41 ST-Elevation Myocardial Infarction (STEMI) The elderly are the highest risk group with STEMI, accounting for more than 50% of all deaths during hospitalizations for acute MI. Although patients aged 75 years or older constitute just 6.1% of the American population, they account for 36% of acute MIs and 60% of the deaths.42 The clinical presentation of elderly patients with acute MI is often atypical. The presentation is frequently late; one study showed that 30% of elderly patients present more than 6 hours after MI-onset. The elderly patient with acute MI is more often managed by a non-cardiologist, and is more frequently admitted to hospitals without catheterization facilities.43 The elderly represent the largest identifiable demographic subgroup with an exceptionally high case fatality rate. The in-hospital mortality rate is 25% in patients aged 80–84 years, and 30% in patients over the age of 85. Consequently, few randomized trials testing new devices or drugs enroll elderly patients with acute MI.42–44 As a result, existing therapeutic recommendations for managing acute MI in the very elderly have been extrapolated from studies conducted in younger patients. Of course, the validity of this premise may be incorrect, and can be fatally criticized on the grounds that the elderly have both markedly increased risks and benefits compared to younger patients. There is no logical reason to presume that judgments that are optimal for younger, lower-risk patients are also the best ones for older patients. For example, increasing age is associated with an exponential rise in case fatality rates following STEMI. The important implication of this progressive age-related decline in post-MI prognosis is that older patients have potentially more to gain than do younger patients from revascularization with PCI. Precisely how the risk and benefits balance, however, has never been formally tested in a clinical trial. Thrombolysis Thrombolysis is not commonly utilized in the elderly age group in contemporary practice. The foremost reasons center on concerns regarding increased bleeding, intracranial hemorrhage and higher in-hospital mortality. Furthermore, a large body of evidence exists that questions its efficacy in the elderly patient,45–48 although some continue to make a case for its potential utility.49 In large part, the lack of enthusiasm for this form of therapy is based on: (1) concern about the risk of internal bleeding, especially intracranial hemorrhage; and (2) clinical evidence that PCI is more beneficial. Numerous trials and meta-analyses have demonstrated the superior benefit of primary PCI. Van der Werf44 showed that age is the single most important risk factor for mortality in STEMI patients treated with thrombolytic therapy. Lee43 demonstrated that the elderly have the highest incidence of MACE when STEMI is treated with thrombolytic agents, including intracranial hemorrhage (3.3%), bleeding requiring transfusion (greater than 20%), cardiac rupture, atrial fibrillation and congestive heart failure. The figures probably underestimate these risks, since the study groups in randomized clinical trials tend to underrepresent the elderly population, who are typically excluded due to concerns of increased bleeding and other vascular complications. Consequently, recent research has focused on increasing the rate and speed of reperfusion without increased bleeding risk. In Gusto V, 50 patients over the age of 75 years remained at increased risk of intracranial hemorrhage with the combination of full-dose abciximab and half-dose reteplase versus full-dose reteplase. These study results suggest that mechanical reperfusion probably continues to offer significant benefit over thrombolytic therapy in the elderly population. However, continued research into combining thrombolysis and PCI is ongoing, and some prominent investigators have suggested that facilitated PCI may eventually offer a beneficial strategy.51 In the ongoing FINESSE trial,52 only patients > 60 years of age are enrolled, providing an excellent opportunity to answer this question. However, recent European guidelines discount this approach.48 Additionally, the early termination of the ASSENT-4 study suggests that little or no therapeutic benefit exists in the STEMI population generally. Primary PCI Primary PCI for STEMI is routinely employed in selected elderly patients, and has been shown conclusively to be more beneficial in this high-risk group than thrombolytic therapy.49,51 However, appropriate case selection in this patient group can be complex.53–56 No published data exist that characterize elderly MI patients not treated with PCI or thrombolysis, but all clinicians have made the decision to treat an acute infarction with intravenous heparin and anti-ischemic medications only from time to time. In some cases, this course is selected consequent to baseline mental status, while in others, it may be due to substantial coexisting medical problems. In the Gusto IIb trial,57 1,138 patients with STEMI were randomized to receive primary angioplasty or thrombolytic therapy with t-PA. The primary composite endpoint of death, reinfarction or stroke was significantly reduced in those patients randomized to angioplasty (9.6% vs. 13.7%; p = 0.033). Importantly, in a prospectively defined group of 300 patients > 70 years of age, there was a strong trend favoring angioplasty. However, it most be noted that these were carefully selected elderly patients, few of whom were older than 80 years of age. A multivariate model predicting survival after PCI in STEMI based on data from the NCDR registry was presented by Klein and colleagues.58 In this model, cardiogenic shock was the clinical variable most strongly predictive of mortality. However, age greater than 65 years was the second most strongly predictive independent variable, being more predictive than the occurrence of multivessel disease, anterior MI, or gender — features which have received far more emphasis. In the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial,59 2,082 patients with acute MI were randomized to balloon angioplasty, angioplasty plus abciximab, stenting alone, or stenting plus abciximab. One-year mortality increased with increasing age greater than or equal to 65 years (1.6% for patients 75 years old; p = 0.0001). Stenting was beneficial in relation to balloon angioplasty in all age groups; importantly, patients greater than or equal to age 65 years enjoyed as much of a relative benefit as those 60 In the ADMIRAL trial,61 300 patients were randomized to either abciximab plus stenting or stenting alone. Better clinical and angiographic outcomes were observed in the abciximab-treated group. Age > 65 years was associated with significantly better 30-day and 6-month outcomes with abciximab. Interestingly, patients aged 62 A recent report63 from the PAMI trials is suggestive that elderly patients, as a consequence of their strong association with increased GI bleeding, have a prolonged hospital stay and increased mortality when treated with primary angioplasty. Elderly women, especially those who do not undergo acute intervention, may be at the highest risk.64 Article Continued in Part II of II
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