Drug Therapy

Efforts to modify the relentless course of Alzheimer disease have until now been based on altering the production or clearance of beta-amyloid, the protein found in plaques in the brains of patients with the disease. Results have been disappointing, possibly because our models of the disease—mostly based on the rare, inherited form—may not be applicable to the much more common sporadic form.

Ely Lilly’s recent announcement that it is halting research into semagacestat, a drug designed to reduce amyloid production, only cast further doubt on viability of the amyloid hypothesis as a framework for effective treatments for Alzheimer disease.

Because of the close association of sporadic Alzheimer disease with vascular disease and type 2 diabetes mellitus, increased efforts to treat and prevent these conditions may be the best approach to reducing the incidence of Alzheimer disease.

This article will discuss current thinking of the pathophysiology of Alzheimer disease, with special attention to potential prevention and treatment strategies.

THE CANONICAL VIEW: AMYLOID IS THE CAUSE

The canonical view is that the toxic effects of beta-amyloid are the cause of neuronal dysfunction and loss in Alzheimer disease.

Beta-amyloid is a small peptide, 38 to 42 amino acids long, that accumulates in the extracellular plaque that characterizes Alzheimer pathology. Small amounts of extracellular beta-amyloid can be detected in the brains of elderly people who die of other causes, but the brains of people who die with severe Alzheimer disease show extensive accumulation of plaques.

The amyloid precursor protein is cleaved by normal constitutive enzymes, leaving beta-amyloid as a fragment. The beta-amyloid forms into fibrillar aggregations, which further clump into the extracellular plaque. Plaques can occur in the normal aging process in relatively low amounts. However, in Alzheimer disease, through some unknown trigger, the immune system appears to become activated in reference to the plaque. Microglial cells—the brain’s macrophages—invade the plaque and trigger a cycle of inflammation. The inflammation and its by-products cause local neuronal damage, which seems to propagate the inflammatory cycle to an even greater extent through a feed-forward loop. The damage leads to metabolic stress in the neuron and collapse of the cytoskeleton into a neurofibrillary tangle. Once the neurofibrillary tangle is forming, the neuron is probably on the path to certain death.

This pathway might be interrupted at several points, and in fact, much of the drug development world is working on possible ways to do so.

GENETIC VS SPORADIC DISEASE: WHAT ARE THE KEY DIFFERENCES?

Although the autosomal dominant form of the disease accounts for probably only 1% or 2% of all cases of Alzheimer disease, most animal models and hence much of the basic research and drug testing in Alzheimer disease are based on those dominant mutations. The pathology—the plaques and tangles—in Alzheimer disease in older adults is identical to that in younger adults, but the origins of the disease may not be the same. Therefore, the experimental model for one may not be relevant to the other.

In the last several years, some have questioned whether the amyloid hypothesis applies to all Alzheimer disease.^1,2 Arguments go back to at least 2002, when Bishop and Robinson in an article entitled “The amyloid hypothesis: Let sleeping dogmas lie?”³ criticized the hypothesis and suggested that the beta-amyloid peptide appeared to be neuroprotective, not neurotoxic, in most situations. They suggested we await the outcome of antiamyloid therapeutic trials to determine whether the amyloid hypothesis truly explains the disorder.

The antiamyloid trials have now been under way for some time, and we have no definitive answer. Data from the phase II study of the monoclonal antibody agent bapineuzumab suggests there might be some small clinical impact of removing amyloid from the brain through immunotherapy mechanisms, but the benefits thus far are not robust.

COULD AMYLOID BE NEUROPROTECTIVE?

A pivotal question might be, “What if sick neurons made amyloid, instead of amyloid making neurons sick?” A corollary question is, “What if the effect were bidirectional?”

It is possible that in certain concentrations amyloid is neurotoxic, but in other concentrations, it actually facilitates neuronal repair, healing, and connection.

REDUCING METABOLIC STRESS: THE KEY TO PREVENTION?

If our current models of drug therapy are not effective against sporadic Alzheimer disease, perhaps focusing on prevention would be more fruitful.

Consider diabetes mellitus as an analogy. Its manifestations include polydipsia, polyuria, fatigue, and elevated glucose and hemoglobin A^1c. Its complications are cardiovascular disease, nephropathy, and retinopathy. Yet diabetes mellitus encompasses two different diseases—type 1 and type 2—with different underlying pathophysiology. We do not treat them the same way. We may be moving toward a similar view of Alzheimer disease.

Links have been hypothesized between vascular risks and dementia. Diabetes, hypertension, dyslipidemia, and obesity might lead to dementia in a process abetted by oxidative stress, endothelial dysfunction, insulin resistance, inflammation, adiposity, and subcortical vascular disease. All of these could be targets of intervention to prevent and treat dementia.⁴

Instead of a beta-amyloid trigger, let us hypothesize that metabolic stress is the initiating element of the Alzheimer cascade, which then triggers beta-amyloid overproduction or underclearance, and the immune activation damages neurons. By lessening metabolic stress or by preventing immune activation, it may, in theory, be possible to prevent neurons from entering into the terminal pathway of tangle formation and cell death.

LINKS BETWEEN ALZHEIMER DISEASE AND DIABETES

Rates of dementia of all causes are higher in people with diabetes. The strongest effect has been noted in vascular dementia, but Alzheimer disease was also found to be associated with diabetes.⁵ The Framingham Heart Study⁶ found the association between dementia and diabetes was significant only when other risk factors for Alzheimer disease were minimal: in an otherwise healthy population, diabetes alone appears to trigger the risk for dementia. But in a population with a lot of vascular comorbidities, the association between diabetes and dementia is not as clear. Perhaps the magnitude of the risk is overwhelmed by greater cerebrovascular and cardiovascular morbidity.

A systematic review⁷ supported the notion that the risk of dementia is higher in people with diabetes, and even raised the issue of whether we should consider Alzheimer disease “type 3 diabetes.”

Testing of the reverse hypothesis—diabetes is more common in people with Alzheimer disease—also is supportive: diabetes mellitus and even impaired fasting glucose are approximately twice as common in people with Alzheimer disease than in those without.⁸ Fasting blood glucose levels increase steadily with age, but after age 65, they are higher in people with Alzheimer disease than in those without.

Glucose has some direct effects on brain metabolism that might explain the higher risk. Chronic hyperglycemia is associated with excessive production of free radicals, which leads to reactive oxygen species. These are toxic to neuronal membranes as well as to mitochondria, where many of the reactive oxygen species are generated. Free radicals also facilitate the inflammatory response.

We also see greater neuronal and mitochondrial calcium influx in the presence of hyperglycemia. The excess calcium interferes with mitochondrial metabolism and may trigger the cascade of apoptosis when it reaches critical levels in neurons.

Chronic hyperglycemia is also associated with increased advanced glycation end-products. These are toxic molecules produced by the persistent exposure of proteins to high sugar levels and may be facilitated by the presence of reactive oxygen species that catalyze the reactions between the sugars and the peptides. Glycation end-products are commonly recognized as the same as those occurring during browning of meat (the Maillard reaction).

Hyperglycemia also potentiates neuronal damage from ischemia. Animal experiments show that brain infarction in the presence of hyperglycemia results in worse damage than the same degree of ischemia in the absence of hyperglycemia. Hyperglycemia may exaggerate other blows to neuronal function such as those from small strokes or microvascular ischemia.

AN ALTERNATIVE TO THE AMYLOID HYPOTHESIS: THE ‘MITOCHONDRIAL CASCADE HYPOTHESIS’

Swerdlow and Khan⁹ have proposed an alternative to the amyloid hypothesis as the cause of Alzheimer disease, known as the “mitochondrial cascade hypothesis.” According to this model, as we age we accumulate more wear-and-tear from oxidative mitochondrial damage, especially the accumulation of toxins leading to reduced cell metabolic activity. This triggers the “3-R response”:

Reset. When toxins alter cell metabolism, neurons try to repair themselves by manufacturing beta-amyloid, which is a “repair-and-reset” synaptic signaling molecule that reduces energy production. Under the lower energy state, beta-pleated sheets develop from beta-amyloid, which aggregate and form amyloid plaque.

Remove. Many cells undergo programmed death when faced with oxidative stress. The first step in neuronal loss is reduced synaptic connections and, hence, losses in neuronal communication. This results in impaired cognition.

Replace. Some cells that are faced with metabolic stress re-enter the cell cycle by undergoing cell division. Neurons, however, are terminally postmitotic and die if they try to divide: by synthesizing cell division proteins, duplicating chromosomes, and reorganizing the complex internal structure, the cell cannot work properly and cell division fails. In the mitochondrial cascade hypothesis, neurofibrillary tangles result from this attempted remodeling of the cytoskeletal filaments, furthering neuronal dysfunction.

ALZHEIMER DISEASE AND STROKE: MORE ALIKE THAN WE THOUGHT?

Although historically clinicians and researchers have tried to distinguish between Alzheimer disease and vascular dementia, growing evidence indicates that the two disorders overlap significantly and that the pathologies may be synergistic.

Alzheimer disease has been hypothesized as being a vascular disorder.¹⁰ It shares many of the risk factors of vascular disease, and preclinical detection of Alzheimer disease is possible from measurements of regional cerebral perfusion. Cerebrovascular and neurodegenerative pathology are parallel in Alzheimer disease and vascular disease.

Pure Alzheimer disease and vascular disease are two ends of a pathologic continuum.¹¹ At one end is “pure” Alzheimer disease, in which patients die only with histologic findings of plaques and neurofibrillary tangles. This form may occur only in patients with the autosomal dominant early-onset form. At the other end of the spectrum are people who have serious vascular disease, multiple strokes, and microvascular ischemia and who die demented but with no evidence of the plaques and tangles of Alzheimer disease.

Between these poles is a spectrum of overlapping pathology that is either Alzheimer disease-dominant or vascular disease-dominant, with varying degrees of amyloid plaque and evidence of microvascular infarcts. Cerebral amyloid angiopathy (the accumulation of beta-amyloid in the wall of arteries in the brain) bridges the syndromes.¹² In some drug studies that attempted removing amyloid from the brain, vascular permeability was altered, resulting in brain edema.

Along the same lines as Kalaria’s model,¹¹ Snowden et al¹³ found at autopsy of aged Catholic nuns that for some the accumulation of Alzheimer pathology alone was insufficient to cause dementia, but dementia was nearly universal in nuns with the same burden of Alzheimer pathology commingled with vascular pathology.

DOES INFLAMMATION PLAY A ROLE?

The inflammatory state is a recognized risk factor for Alzheimer disease, but the clinical data are mixed. Epidemiologic evidence is strong: patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for chronic, systemic inflammatory diseases (eg, arthritis) have a 45% to 60% reduced risk for Alzheimer disease.^14,15

However, multiple clinical trials in patients with Alzheimer disease have failed to show a benefit of taking anti-inflammatory drugs. One preliminary report suggested that indomethacin (Indocin) might offer benefit, but because of gastrointestinal side effects its usefulness in an elderly population is limited.

Diabetes and inflammation are also closely linked: hyperinsulinemia is proinflammatory, promoting the formation of reactive oxygen species, inhibiting the degradation of oxidized proteins, and increasing the risk for lipid per-oxidation. Insulin acts synergistically with endotoxins to raise inflammatory markers, eg, proinflammatory cytokines and C-reactive protein.¹⁶

It is possible that anti-inflammatory drugs may not work in Alzheimer disease because inflammation in the brain is mediated more by microglial cells than by prostaglandin pathways. In Alzheimer disease, inflammation is mediated by activated microglial cells, which invade plaques with their processes; these are not evident in the diffuse beta-amyloid-rich plaques seen in typical aging. The trigger for their activation is unclear, but the activated microglial cells and the invasion of plaques are seen in transgenic mouse models of Alzheimer disease, and activation is seen when beta-amyloid is injected into the brain of a healthy mouse.¹⁷

Activated microglial cells enlarge and their metabolic rate increases, with a surge in the production of proteins and other protein-mediated inflammatory markers such as alpha-antichymotrypsin, alpha-antitrypsin, serum amyloid P, C-reactive protein, nitric oxide, and proinflammatory cytokines. It is unlikely that it is healthy for cells to be exposed to these inflammatory products. Some of the cytokines are now targets of drug development for Alzheimer disease, and agents targeting these pathways have already been developed for connective tissue diseases.

In a controversial pilot study, Tobinick et al¹⁸ studied the use of etanercept (Enbrel), an inhibitor of tumor necrosis factor-alpha (an inflammatory cytokine). They injected etanercept weekly into the spinal canal in 15 patients with mild to severe Alzheimer disease, for 6 months. Patients improved in the Mini-Mental State Examination by more than two points during the study. Patent issues surrounding use of this drug in Alzheimer disease may delay further trials.

Thiazolidinediones block microglial cell activation

The reactive microglial phenotype can be prevented in cell culture by peroxisome proliferator-activated receptor (PPAR) gamma agonists. These include the antidiabetic thiazolidinediones such as pioglitazone (Actos), troglitazone (Rezulin), and rosiglitazone (Avandia), and indomethacin and other NSAIDs.

Using a Veterans Administration database of more than 142,000 patients, Miller et al¹⁹ retrospectively found that patients who took a thiazolidinedione for diabetes had a 20% lower risk of developing Alzheimer disease compared with users of insulin or metformin (Glucophage).

However, rosiglitazone showed no benefit against Alzheimer disease in a large clinical trial,²⁰ but this may be because it is rapidly cleared from the brain. Pioglitazone is not actively exported from the brain, so it may be a better candidate, but pharmaceutical industry interest in this agent is low because its patent will soon expire.

Fish oil is another PPAR-gamma agonist, and some studies indicate that eating fish may protect against developing Alzheimer disease; it may also be therapeutic if the disease is present. Double-blind controlled studies have not been carried out and likely will not because of patent issues: the costs of such studies are high, and the potential payback is low.

ESTROGEN: PROTECTIVE OR NOT?

Whether taking estrogen is a risk factor or is protective has not yet been determined. Estrogen directly affects neurons. It increases the number of dendritic spines, which are associated with improved memory. Meta-analyses suggest that hormone replacement therapy reduces the risk of dementia by about one-third. ^21,22 Both positive and negative prospective studies exist, but all are complicated by serious methodologic flaws.^23,24

Combined analysis of about 7,500 women from two double-blind, randomized, placebo-controlled trials of the Women’s Health Initiative Memory Study found that the risks of dementia and mild cognitive impairment were increased by hormone replacement therapy. The hazard ratio for dementia was found to be 1.76 (P < .005), amounting to 23 new cases of dementia per 10,000 prescriptions annually.²⁵

Patient selection may account for the conflicting results in different studies. Epidemiologic studies consisted mostly of newly postmenopausal women and those who were being treated for symptoms of vasomotor instability. In contrast, the Women’s Health Initiative enrolled only women older than 65 and excluded women with vasomotor instability. Other studies indicate that the greatest cognitive improvements with hormone therapies are seen in women with vasomotor symptoms.

WHICH RISK FACTORS CAN WE CONTROL?

In summary, some of the risk factors for Alzheimer disease can be modified if we do the following.

Aggressively manage diabetes and cardiovascular disease. Vascular risk factors significantly increase dementia risk, providing good targets for prevention: clinicians should aggressively help their patients control diabetes, hypertension, and hyperlipidemia.²⁶ However, aggressive control of hypertension in a patient with already-existing dementia may exacerbate the condition, so caution is warranted.

Optimize diet. Dietary measures include high intake of antioxidants (which are especially high in brightly colored and tart-flavored fruits and vegetables) and polyunsaturated fats.²⁶ Eating a Mediterranean-type diet that includes a high intake of cold-water ocean fish is recommended. Fish should not be fried: the high temperatures may destroy the omega-3 fatty acids, and the high fat content may inhibit their absorption.

Weigh the risks and benefits of estrogen. Although estrogen replacement therapy for postmenopausal women has had mixed results for controlling dementia, it appears to be clinically indicated to control vasomotor symptoms and likely does not increase the risk of dementia for newly menopausal women. Risks and benefits should be carefully weighed for each patient.

Optimize exercise. People who are physically active in midlife have a lower risk of Alzheimer disease.²⁷ Those who adopt new physical activity late in life may also gain some protective or restorative benefit.²⁸

Many measures, such as taking anti-inflammatory or antihypertensive drugs, probably have a very small incremental benefit over time, so it is difficult to measure significant effects during the course of a typical clinical trial.

Clinicians are already recommending actions to reduce the risk of dementia by focusing on lowering cardiovascular risk. Hopefully, as these actions become more commonly practiced as lifelong habits in those reaching the age of risk for Alzheimer disease, we will see a reduced incidence of that devastating and much-feared illness.

Efforts to modify the relentless course of Alzheimer disease have until now been based on altering the production or clearance of beta-amyloid, the protein found in plaques in the brains of patients with the disease. Results have been disappointing, possibly because our models of the disease—mostly based on the rare, inherited form—may not be applicable to the much more common sporadic form.

Ely Lilly’s recent announcement that it is halting research into semagacestat, a drug designed to reduce amyloid production, only cast further doubt on viability of the amyloid hypothesis as a framework for effective treatments for Alzheimer disease.

Because of the close association of sporadic Alzheimer disease with vascular disease and type 2 diabetes mellitus, increased efforts to treat and prevent these conditions may be the best approach to reducing the incidence of Alzheimer disease.

This article will discuss current thinking of the pathophysiology of Alzheimer disease, with special attention to potential prevention and treatment strategies.

THE CANONICAL VIEW: AMYLOID IS THE CAUSE

The canonical view is that the toxic effects of beta-amyloid are the cause of neuronal dysfunction and loss in Alzheimer disease.

Beta-amyloid is a small peptide, 38 to 42 amino acids long, that accumulates in the extracellular plaque that characterizes Alzheimer pathology. Small amounts of extracellular beta-amyloid can be detected in the brains of elderly people who die of other causes, but the brains of people who die with severe Alzheimer disease show extensive accumulation of plaques.

The amyloid precursor protein is cleaved by normal constitutive enzymes, leaving beta-amyloid as a fragment. The beta-amyloid forms into fibrillar aggregations, which further clump into the extracellular plaque. Plaques can occur in the normal aging process in relatively low amounts. However, in Alzheimer disease, through some unknown trigger, the immune system appears to become activated in reference to the plaque. Microglial cells—the brain’s macrophages—invade the plaque and trigger a cycle of inflammation. The inflammation and its by-products cause local neuronal damage, which seems to propagate the inflammatory cycle to an even greater extent through a feed-forward loop. The damage leads to metabolic stress in the neuron and collapse of the cytoskeleton into a neurofibrillary tangle. Once the neurofibrillary tangle is forming, the neuron is probably on the path to certain death.

This pathway might be interrupted at several points, and in fact, much of the drug development world is working on possible ways to do so.

GENETIC VS SPORADIC DISEASE: WHAT ARE THE KEY DIFFERENCES?

Although the autosomal dominant form of the disease accounts for probably only 1% or 2% of all cases of Alzheimer disease, most animal models and hence much of the basic research and drug testing in Alzheimer disease are based on those dominant mutations. The pathology—the plaques and tangles—in Alzheimer disease in older adults is identical to that in younger adults, but the origins of the disease may not be the same. Therefore, the experimental model for one may not be relevant to the other.

In the last several years, some have questioned whether the amyloid hypothesis applies to all Alzheimer disease.^1,2 Arguments go back to at least 2002, when Bishop and Robinson in an article entitled “The amyloid hypothesis: Let sleeping dogmas lie?”³ criticized the hypothesis and suggested that the beta-amyloid peptide appeared to be neuroprotective, not neurotoxic, in most situations. They suggested we await the outcome of antiamyloid therapeutic trials to determine whether the amyloid hypothesis truly explains the disorder.

The antiamyloid trials have now been under way for some time, and we have no definitive answer. Data from the phase II study of the monoclonal antibody agent bapineuzumab suggests there might be some small clinical impact of removing amyloid from the brain through immunotherapy mechanisms, but the benefits thus far are not robust.

COULD AMYLOID BE NEUROPROTECTIVE?

A pivotal question might be, “What if sick neurons made amyloid, instead of amyloid making neurons sick?” A corollary question is, “What if the effect were bidirectional?”

It is possible that in certain concentrations amyloid is neurotoxic, but in other concentrations, it actually facilitates neuronal repair, healing, and connection.

REDUCING METABOLIC STRESS: THE KEY TO PREVENTION?

If our current models of drug therapy are not effective against sporadic Alzheimer disease, perhaps focusing on prevention would be more fruitful.

Consider diabetes mellitus as an analogy. Its manifestations include polydipsia, polyuria, fatigue, and elevated glucose and hemoglobin A^1c. Its complications are cardiovascular disease, nephropathy, and retinopathy. Yet diabetes mellitus encompasses two different diseases—type 1 and type 2—with different underlying pathophysiology. We do not treat them the same way. We may be moving toward a similar view of Alzheimer disease.

Links have been hypothesized between vascular risks and dementia. Diabetes, hypertension, dyslipidemia, and obesity might lead to dementia in a process abetted by oxidative stress, endothelial dysfunction, insulin resistance, inflammation, adiposity, and subcortical vascular disease. All of these could be targets of intervention to prevent and treat dementia.⁴

Instead of a beta-amyloid trigger, let us hypothesize that metabolic stress is the initiating element of the Alzheimer cascade, which then triggers beta-amyloid overproduction or underclearance, and the immune activation damages neurons. By lessening metabolic stress or by preventing immune activation, it may, in theory, be possible to prevent neurons from entering into the terminal pathway of tangle formation and cell death.

LINKS BETWEEN ALZHEIMER DISEASE AND DIABETES

Rates of dementia of all causes are higher in people with diabetes. The strongest effect has been noted in vascular dementia, but Alzheimer disease was also found to be associated with diabetes.⁵ The Framingham Heart Study⁶ found the association between dementia and diabetes was significant only when other risk factors for Alzheimer disease were minimal: in an otherwise healthy population, diabetes alone appears to trigger the risk for dementia. But in a population with a lot of vascular comorbidities, the association between diabetes and dementia is not as clear. Perhaps the magnitude of the risk is overwhelmed by greater cerebrovascular and cardiovascular morbidity.

A systematic review⁷ supported the notion that the risk of dementia is higher in people with diabetes, and even raised the issue of whether we should consider Alzheimer disease “type 3 diabetes.”

Testing of the reverse hypothesis—diabetes is more common in people with Alzheimer disease—also is supportive: diabetes mellitus and even impaired fasting glucose are approximately twice as common in people with Alzheimer disease than in those without.⁸ Fasting blood glucose levels increase steadily with age, but after age 65, they are higher in people with Alzheimer disease than in those without.

Glucose has some direct effects on brain metabolism that might explain the higher risk. Chronic hyperglycemia is associated with excessive production of free radicals, which leads to reactive oxygen species. These are toxic to neuronal membranes as well as to mitochondria, where many of the reactive oxygen species are generated. Free radicals also facilitate the inflammatory response.

We also see greater neuronal and mitochondrial calcium influx in the presence of hyperglycemia. The excess calcium interferes with mitochondrial metabolism and may trigger the cascade of apoptosis when it reaches critical levels in neurons.

Chronic hyperglycemia is also associated with increased advanced glycation end-products. These are toxic molecules produced by the persistent exposure of proteins to high sugar levels and may be facilitated by the presence of reactive oxygen species that catalyze the reactions between the sugars and the peptides. Glycation end-products are commonly recognized as the same as those occurring during browning of meat (the Maillard reaction).

Hyperglycemia also potentiates neuronal damage from ischemia. Animal experiments show that brain infarction in the presence of hyperglycemia results in worse damage than the same degree of ischemia in the absence of hyperglycemia. Hyperglycemia may exaggerate other blows to neuronal function such as those from small strokes or microvascular ischemia.

AN ALTERNATIVE TO THE AMYLOID HYPOTHESIS: THE ‘MITOCHONDRIAL CASCADE HYPOTHESIS’

Swerdlow and Khan⁹ have proposed an alternative to the amyloid hypothesis as the cause of Alzheimer disease, known as the “mitochondrial cascade hypothesis.” According to this model, as we age we accumulate more wear-and-tear from oxidative mitochondrial damage, especially the accumulation of toxins leading to reduced cell metabolic activity. This triggers the “3-R response”:

Reset. When toxins alter cell metabolism, neurons try to repair themselves by manufacturing beta-amyloid, which is a “repair-and-reset” synaptic signaling molecule that reduces energy production. Under the lower energy state, beta-pleated sheets develop from beta-amyloid, which aggregate and form amyloid plaque.

Remove. Many cells undergo programmed death when faced with oxidative stress. The first step in neuronal loss is reduced synaptic connections and, hence, losses in neuronal communication. This results in impaired cognition.

Replace. Some cells that are faced with metabolic stress re-enter the cell cycle by undergoing cell division. Neurons, however, are terminally postmitotic and die if they try to divide: by synthesizing cell division proteins, duplicating chromosomes, and reorganizing the complex internal structure, the cell cannot work properly and cell division fails. In the mitochondrial cascade hypothesis, neurofibrillary tangles result from this attempted remodeling of the cytoskeletal filaments, furthering neuronal dysfunction.

ALZHEIMER DISEASE AND STROKE: MORE ALIKE THAN WE THOUGHT?

Although historically clinicians and researchers have tried to distinguish between Alzheimer disease and vascular dementia, growing evidence indicates that the two disorders overlap significantly and that the pathologies may be synergistic.

Alzheimer disease has been hypothesized as being a vascular disorder.¹⁰ It shares many of the risk factors of vascular disease, and preclinical detection of Alzheimer disease is possible from measurements of regional cerebral perfusion. Cerebrovascular and neurodegenerative pathology are parallel in Alzheimer disease and vascular disease.

Pure Alzheimer disease and vascular disease are two ends of a pathologic continuum.¹¹ At one end is “pure” Alzheimer disease, in which patients die only with histologic findings of plaques and neurofibrillary tangles. This form may occur only in patients with the autosomal dominant early-onset form. At the other end of the spectrum are people who have serious vascular disease, multiple strokes, and microvascular ischemia and who die demented but with no evidence of the plaques and tangles of Alzheimer disease.

Between these poles is a spectrum of overlapping pathology that is either Alzheimer disease-dominant or vascular disease-dominant, with varying degrees of amyloid plaque and evidence of microvascular infarcts. Cerebral amyloid angiopathy (the accumulation of beta-amyloid in the wall of arteries in the brain) bridges the syndromes.¹² In some drug studies that attempted removing amyloid from the brain, vascular permeability was altered, resulting in brain edema.

Along the same lines as Kalaria’s model,¹¹ Snowden et al¹³ found at autopsy of aged Catholic nuns that for some the accumulation of Alzheimer pathology alone was insufficient to cause dementia, but dementia was nearly universal in nuns with the same burden of Alzheimer pathology commingled with vascular pathology.

DOES INFLAMMATION PLAY A ROLE?

The inflammatory state is a recognized risk factor for Alzheimer disease, but the clinical data are mixed. Epidemiologic evidence is strong: patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for chronic, systemic inflammatory diseases (eg, arthritis) have a 45% to 60% reduced risk for Alzheimer disease.^14,15

However, multiple clinical trials in patients with Alzheimer disease have failed to show a benefit of taking anti-inflammatory drugs. One preliminary report suggested that indomethacin (Indocin) might offer benefit, but because of gastrointestinal side effects its usefulness in an elderly population is limited.

Diabetes and inflammation are also closely linked: hyperinsulinemia is proinflammatory, promoting the formation of reactive oxygen species, inhibiting the degradation of oxidized proteins, and increasing the risk for lipid per-oxidation. Insulin acts synergistically with endotoxins to raise inflammatory markers, eg, proinflammatory cytokines and C-reactive protein.¹⁶

It is possible that anti-inflammatory drugs may not work in Alzheimer disease because inflammation in the brain is mediated more by microglial cells than by prostaglandin pathways. In Alzheimer disease, inflammation is mediated by activated microglial cells, which invade plaques with their processes; these are not evident in the diffuse beta-amyloid-rich plaques seen in typical aging. The trigger for their activation is unclear, but the activated microglial cells and the invasion of plaques are seen in transgenic mouse models of Alzheimer disease, and activation is seen when beta-amyloid is injected into the brain of a healthy mouse.¹⁷

Activated microglial cells enlarge and their metabolic rate increases, with a surge in the production of proteins and other protein-mediated inflammatory markers such as alpha-antichymotrypsin, alpha-antitrypsin, serum amyloid P, C-reactive protein, nitric oxide, and proinflammatory cytokines. It is unlikely that it is healthy for cells to be exposed to these inflammatory products. Some of the cytokines are now targets of drug development for Alzheimer disease, and agents targeting these pathways have already been developed for connective tissue diseases.

In a controversial pilot study, Tobinick et al¹⁸ studied the use of etanercept (Enbrel), an inhibitor of tumor necrosis factor-alpha (an inflammatory cytokine). They injected etanercept weekly into the spinal canal in 15 patients with mild to severe Alzheimer disease, for 6 months. Patients improved in the Mini-Mental State Examination by more than two points during the study. Patent issues surrounding use of this drug in Alzheimer disease may delay further trials.

Thiazolidinediones block microglial cell activation

The reactive microglial phenotype can be prevented in cell culture by peroxisome proliferator-activated receptor (PPAR) gamma agonists. These include the antidiabetic thiazolidinediones such as pioglitazone (Actos), troglitazone (Rezulin), and rosiglitazone (Avandia), and indomethacin and other NSAIDs.

Using a Veterans Administration database of more than 142,000 patients, Miller et al¹⁹ retrospectively found that patients who took a thiazolidinedione for diabetes had a 20% lower risk of developing Alzheimer disease compared with users of insulin or metformin (Glucophage).

However, rosiglitazone showed no benefit against Alzheimer disease in a large clinical trial,²⁰ but this may be because it is rapidly cleared from the brain. Pioglitazone is not actively exported from the brain, so it may be a better candidate, but pharmaceutical industry interest in this agent is low because its patent will soon expire.

Fish oil is another PPAR-gamma agonist, and some studies indicate that eating fish may protect against developing Alzheimer disease; it may also be therapeutic if the disease is present. Double-blind controlled studies have not been carried out and likely will not because of patent issues: the costs of such studies are high, and the potential payback is low.

ESTROGEN: PROTECTIVE OR NOT?

Whether taking estrogen is a risk factor or is protective has not yet been determined. Estrogen directly affects neurons. It increases the number of dendritic spines, which are associated with improved memory. Meta-analyses suggest that hormone replacement therapy reduces the risk of dementia by about one-third. ^21,22 Both positive and negative prospective studies exist, but all are complicated by serious methodologic flaws.^23,24

Combined analysis of about 7,500 women from two double-blind, randomized, placebo-controlled trials of the Women’s Health Initiative Memory Study found that the risks of dementia and mild cognitive impairment were increased by hormone replacement therapy. The hazard ratio for dementia was found to be 1.76 (P < .005), amounting to 23 new cases of dementia per 10,000 prescriptions annually.²⁵

Patient selection may account for the conflicting results in different studies. Epidemiologic studies consisted mostly of newly postmenopausal women and those who were being treated for symptoms of vasomotor instability. In contrast, the Women’s Health Initiative enrolled only women older than 65 and excluded women with vasomotor instability. Other studies indicate that the greatest cognitive improvements with hormone therapies are seen in women with vasomotor symptoms.

WHICH RISK FACTORS CAN WE CONTROL?

In summary, some of the risk factors for Alzheimer disease can be modified if we do the following.

Aggressively manage diabetes and cardiovascular disease. Vascular risk factors significantly increase dementia risk, providing good targets for prevention: clinicians should aggressively help their patients control diabetes, hypertension, and hyperlipidemia.²⁶ However, aggressive control of hypertension in a patient with already-existing dementia may exacerbate the condition, so caution is warranted.

Optimize diet. Dietary measures include high intake of antioxidants (which are especially high in brightly colored and tart-flavored fruits and vegetables) and polyunsaturated fats.²⁶ Eating a Mediterranean-type diet that includes a high intake of cold-water ocean fish is recommended. Fish should not be fried: the high temperatures may destroy the omega-3 fatty acids, and the high fat content may inhibit their absorption.

Weigh the risks and benefits of estrogen. Although estrogen replacement therapy for postmenopausal women has had mixed results for controlling dementia, it appears to be clinically indicated to control vasomotor symptoms and likely does not increase the risk of dementia for newly menopausal women. Risks and benefits should be carefully weighed for each patient.

Optimize exercise. People who are physically active in midlife have a lower risk of Alzheimer disease.²⁷ Those who adopt new physical activity late in life may also gain some protective or restorative benefit.²⁸

Many measures, such as taking anti-inflammatory or antihypertensive drugs, probably have a very small incremental benefit over time, so it is difficult to measure significant effects during the course of a typical clinical trial.

Clinicians are already recommending actions to reduce the risk of dementia by focusing on lowering cardiovascular risk. Hopefully, as these actions become more commonly practiced as lifelong habits in those reaching the age of risk for Alzheimer disease, we will see a reduced incidence of that devastating and much-feared illness.

Efforts to modify the relentless course of Alzheimer disease have until now been based on altering the production or clearance of beta-amyloid, the protein found in plaques in the brains of patients with the disease. Results have been disappointing, possibly because our models of the disease—mostly based on the rare, inherited form—may not be applicable to the much more common sporadic form.

Ely Lilly’s recent announcement that it is halting research into semagacestat, a drug designed to reduce amyloid production, only cast further doubt on viability of the amyloid hypothesis as a framework for effective treatments for Alzheimer disease.

Because of the close association of sporadic Alzheimer disease with vascular disease and type 2 diabetes mellitus, increased efforts to treat and prevent these conditions may be the best approach to reducing the incidence of Alzheimer disease.

This article will discuss current thinking of the pathophysiology of Alzheimer disease, with special attention to potential prevention and treatment strategies.

THE CANONICAL VIEW: AMYLOID IS THE CAUSE

The canonical view is that the toxic effects of beta-amyloid are the cause of neuronal dysfunction and loss in Alzheimer disease.

Beta-amyloid is a small peptide, 38 to 42 amino acids long, that accumulates in the extracellular plaque that characterizes Alzheimer pathology. Small amounts of extracellular beta-amyloid can be detected in the brains of elderly people who die of other causes, but the brains of people who die with severe Alzheimer disease show extensive accumulation of plaques.

The amyloid precursor protein is cleaved by normal constitutive enzymes, leaving beta-amyloid as a fragment. The beta-amyloid forms into fibrillar aggregations, which further clump into the extracellular plaque. Plaques can occur in the normal aging process in relatively low amounts. However, in Alzheimer disease, through some unknown trigger, the immune system appears to become activated in reference to the plaque. Microglial cells—the brain’s macrophages—invade the plaque and trigger a cycle of inflammation. The inflammation and its by-products cause local neuronal damage, which seems to propagate the inflammatory cycle to an even greater extent through a feed-forward loop. The damage leads to metabolic stress in the neuron and collapse of the cytoskeleton into a neurofibrillary tangle. Once the neurofibrillary tangle is forming, the neuron is probably on the path to certain death.

This pathway might be interrupted at several points, and in fact, much of the drug development world is working on possible ways to do so.

GENETIC VS SPORADIC DISEASE: WHAT ARE THE KEY DIFFERENCES?

Although the autosomal dominant form of the disease accounts for probably only 1% or 2% of all cases of Alzheimer disease, most animal models and hence much of the basic research and drug testing in Alzheimer disease are based on those dominant mutations. The pathology—the plaques and tangles—in Alzheimer disease in older adults is identical to that in younger adults, but the origins of the disease may not be the same. Therefore, the experimental model for one may not be relevant to the other.

In the last several years, some have questioned whether the amyloid hypothesis applies to all Alzheimer disease.^1,2 Arguments go back to at least 2002, when Bishop and Robinson in an article entitled “The amyloid hypothesis: Let sleeping dogmas lie?”³ criticized the hypothesis and suggested that the beta-amyloid peptide appeared to be neuroprotective, not neurotoxic, in most situations. They suggested we await the outcome of antiamyloid therapeutic trials to determine whether the amyloid hypothesis truly explains the disorder.

The antiamyloid trials have now been under way for some time, and we have no definitive answer. Data from the phase II study of the monoclonal antibody agent bapineuzumab suggests there might be some small clinical impact of removing amyloid from the brain through immunotherapy mechanisms, but the benefits thus far are not robust.

COULD AMYLOID BE NEUROPROTECTIVE?

A pivotal question might be, “What if sick neurons made amyloid, instead of amyloid making neurons sick?” A corollary question is, “What if the effect were bidirectional?”

It is possible that in certain concentrations amyloid is neurotoxic, but in other concentrations, it actually facilitates neuronal repair, healing, and connection.

REDUCING METABOLIC STRESS: THE KEY TO PREVENTION?

If our current models of drug therapy are not effective against sporadic Alzheimer disease, perhaps focusing on prevention would be more fruitful.

Consider diabetes mellitus as an analogy. Its manifestations include polydipsia, polyuria, fatigue, and elevated glucose and hemoglobin A^1c. Its complications are cardiovascular disease, nephropathy, and retinopathy. Yet diabetes mellitus encompasses two different diseases—type 1 and type 2—with different underlying pathophysiology. We do not treat them the same way. We may be moving toward a similar view of Alzheimer disease.

Links have been hypothesized between vascular risks and dementia. Diabetes, hypertension, dyslipidemia, and obesity might lead to dementia in a process abetted by oxidative stress, endothelial dysfunction, insulin resistance, inflammation, adiposity, and subcortical vascular disease. All of these could be targets of intervention to prevent and treat dementia.⁴

Instead of a beta-amyloid trigger, let us hypothesize that metabolic stress is the initiating element of the Alzheimer cascade, which then triggers beta-amyloid overproduction or underclearance, and the immune activation damages neurons. By lessening metabolic stress or by preventing immune activation, it may, in theory, be possible to prevent neurons from entering into the terminal pathway of tangle formation and cell death.

LINKS BETWEEN ALZHEIMER DISEASE AND DIABETES

Rates of dementia of all causes are higher in people with diabetes. The strongest effect has been noted in vascular dementia, but Alzheimer disease was also found to be associated with diabetes.⁵ The Framingham Heart Study⁶ found the association between dementia and diabetes was significant only when other risk factors for Alzheimer disease were minimal: in an otherwise healthy population, diabetes alone appears to trigger the risk for dementia. But in a population with a lot of vascular comorbidities, the association between diabetes and dementia is not as clear. Perhaps the magnitude of the risk is overwhelmed by greater cerebrovascular and cardiovascular morbidity.

A systematic review⁷ supported the notion that the risk of dementia is higher in people with diabetes, and even raised the issue of whether we should consider Alzheimer disease “type 3 diabetes.”

Testing of the reverse hypothesis—diabetes is more common in people with Alzheimer disease—also is supportive: diabetes mellitus and even impaired fasting glucose are approximately twice as common in people with Alzheimer disease than in those without.⁸ Fasting blood glucose levels increase steadily with age, but after age 65, they are higher in people with Alzheimer disease than in those without.

Glucose has some direct effects on brain metabolism that might explain the higher risk. Chronic hyperglycemia is associated with excessive production of free radicals, which leads to reactive oxygen species. These are toxic to neuronal membranes as well as to mitochondria, where many of the reactive oxygen species are generated. Free radicals also facilitate the inflammatory response.

We also see greater neuronal and mitochondrial calcium influx in the presence of hyperglycemia. The excess calcium interferes with mitochondrial metabolism and may trigger the cascade of apoptosis when it reaches critical levels in neurons.

Chronic hyperglycemia is also associated with increased advanced glycation end-products. These are toxic molecules produced by the persistent exposure of proteins to high sugar levels and may be facilitated by the presence of reactive oxygen species that catalyze the reactions between the sugars and the peptides. Glycation end-products are commonly recognized as the same as those occurring during browning of meat (the Maillard reaction).

Hyperglycemia also potentiates neuronal damage from ischemia. Animal experiments show that brain infarction in the presence of hyperglycemia results in worse damage than the same degree of ischemia in the absence of hyperglycemia. Hyperglycemia may exaggerate other blows to neuronal function such as those from small strokes or microvascular ischemia.

AN ALTERNATIVE TO THE AMYLOID HYPOTHESIS: THE ‘MITOCHONDRIAL CASCADE HYPOTHESIS’

Swerdlow and Khan⁹ have proposed an alternative to the amyloid hypothesis as the cause of Alzheimer disease, known as the “mitochondrial cascade hypothesis.” According to this model, as we age we accumulate more wear-and-tear from oxidative mitochondrial damage, especially the accumulation of toxins leading to reduced cell metabolic activity. This triggers the “3-R response”:

Reset. When toxins alter cell metabolism, neurons try to repair themselves by manufacturing beta-amyloid, which is a “repair-and-reset” synaptic signaling molecule that reduces energy production. Under the lower energy state, beta-pleated sheets develop from beta-amyloid, which aggregate and form amyloid plaque.

Remove. Many cells undergo programmed death when faced with oxidative stress. The first step in neuronal loss is reduced synaptic connections and, hence, losses in neuronal communication. This results in impaired cognition.

Replace. Some cells that are faced with metabolic stress re-enter the cell cycle by undergoing cell division. Neurons, however, are terminally postmitotic and die if they try to divide: by synthesizing cell division proteins, duplicating chromosomes, and reorganizing the complex internal structure, the cell cannot work properly and cell division fails. In the mitochondrial cascade hypothesis, neurofibrillary tangles result from this attempted remodeling of the cytoskeletal filaments, furthering neuronal dysfunction.

ALZHEIMER DISEASE AND STROKE: MORE ALIKE THAN WE THOUGHT?

Although historically clinicians and researchers have tried to distinguish between Alzheimer disease and vascular dementia, growing evidence indicates that the two disorders overlap significantly and that the pathologies may be synergistic.

Alzheimer disease has been hypothesized as being a vascular disorder.¹⁰ It shares many of the risk factors of vascular disease, and preclinical detection of Alzheimer disease is possible from measurements of regional cerebral perfusion. Cerebrovascular and neurodegenerative pathology are parallel in Alzheimer disease and vascular disease.

Pure Alzheimer disease and vascular disease are two ends of a pathologic continuum.¹¹ At one end is “pure” Alzheimer disease, in which patients die only with histologic findings of plaques and neurofibrillary tangles. This form may occur only in patients with the autosomal dominant early-onset form. At the other end of the spectrum are people who have serious vascular disease, multiple strokes, and microvascular ischemia and who die demented but with no evidence of the plaques and tangles of Alzheimer disease.

Between these poles is a spectrum of overlapping pathology that is either Alzheimer disease-dominant or vascular disease-dominant, with varying degrees of amyloid plaque and evidence of microvascular infarcts. Cerebral amyloid angiopathy (the accumulation of beta-amyloid in the wall of arteries in the brain) bridges the syndromes.¹² In some drug studies that attempted removing amyloid from the brain, vascular permeability was altered, resulting in brain edema.

Along the same lines as Kalaria’s model,¹¹ Snowden et al¹³ found at autopsy of aged Catholic nuns that for some the accumulation of Alzheimer pathology alone was insufficient to cause dementia, but dementia was nearly universal in nuns with the same burden of Alzheimer pathology commingled with vascular pathology.

DOES INFLAMMATION PLAY A ROLE?

The inflammatory state is a recognized risk factor for Alzheimer disease, but the clinical data are mixed. Epidemiologic evidence is strong: patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for chronic, systemic inflammatory diseases (eg, arthritis) have a 45% to 60% reduced risk for Alzheimer disease.^14,15

However, multiple clinical trials in patients with Alzheimer disease have failed to show a benefit of taking anti-inflammatory drugs. One preliminary report suggested that indomethacin (Indocin) might offer benefit, but because of gastrointestinal side effects its usefulness in an elderly population is limited.

Diabetes and inflammation are also closely linked: hyperinsulinemia is proinflammatory, promoting the formation of reactive oxygen species, inhibiting the degradation of oxidized proteins, and increasing the risk for lipid per-oxidation. Insulin acts synergistically with endotoxins to raise inflammatory markers, eg, proinflammatory cytokines and C-reactive protein.¹⁶

It is possible that anti-inflammatory drugs may not work in Alzheimer disease because inflammation in the brain is mediated more by microglial cells than by prostaglandin pathways. In Alzheimer disease, inflammation is mediated by activated microglial cells, which invade plaques with their processes; these are not evident in the diffuse beta-amyloid-rich plaques seen in typical aging. The trigger for their activation is unclear, but the activated microglial cells and the invasion of plaques are seen in transgenic mouse models of Alzheimer disease, and activation is seen when beta-amyloid is injected into the brain of a healthy mouse.¹⁷

Activated microglial cells enlarge and their metabolic rate increases, with a surge in the production of proteins and other protein-mediated inflammatory markers such as alpha-antichymotrypsin, alpha-antitrypsin, serum amyloid P, C-reactive protein, nitric oxide, and proinflammatory cytokines. It is unlikely that it is healthy for cells to be exposed to these inflammatory products. Some of the cytokines are now targets of drug development for Alzheimer disease, and agents targeting these pathways have already been developed for connective tissue diseases.

In a controversial pilot study, Tobinick et al¹⁸ studied the use of etanercept (Enbrel), an inhibitor of tumor necrosis factor-alpha (an inflammatory cytokine). They injected etanercept weekly into the spinal canal in 15 patients with mild to severe Alzheimer disease, for 6 months. Patients improved in the Mini-Mental State Examination by more than two points during the study. Patent issues surrounding use of this drug in Alzheimer disease may delay further trials.

Thiazolidinediones block microglial cell activation

The reactive microglial phenotype can be prevented in cell culture by peroxisome proliferator-activated receptor (PPAR) gamma agonists. These include the antidiabetic thiazolidinediones such as pioglitazone (Actos), troglitazone (Rezulin), and rosiglitazone (Avandia), and indomethacin and other NSAIDs.

Using a Veterans Administration database of more than 142,000 patients, Miller et al¹⁹ retrospectively found that patients who took a thiazolidinedione for diabetes had a 20% lower risk of developing Alzheimer disease compared with users of insulin or metformin (Glucophage).

However, rosiglitazone showed no benefit against Alzheimer disease in a large clinical trial,²⁰ but this may be because it is rapidly cleared from the brain. Pioglitazone is not actively exported from the brain, so it may be a better candidate, but pharmaceutical industry interest in this agent is low because its patent will soon expire.

Fish oil is another PPAR-gamma agonist, and some studies indicate that eating fish may protect against developing Alzheimer disease; it may also be therapeutic if the disease is present. Double-blind controlled studies have not been carried out and likely will not because of patent issues: the costs of such studies are high, and the potential payback is low.

ESTROGEN: PROTECTIVE OR NOT?

Whether taking estrogen is a risk factor or is protective has not yet been determined. Estrogen directly affects neurons. It increases the number of dendritic spines, which are associated with improved memory. Meta-analyses suggest that hormone replacement therapy reduces the risk of dementia by about one-third. ^21,22 Both positive and negative prospective studies exist, but all are complicated by serious methodologic flaws.^23,24

Combined analysis of about 7,500 women from two double-blind, randomized, placebo-controlled trials of the Women’s Health Initiative Memory Study found that the risks of dementia and mild cognitive impairment were increased by hormone replacement therapy. The hazard ratio for dementia was found to be 1.76 (P < .005), amounting to 23 new cases of dementia per 10,000 prescriptions annually.²⁵

Patient selection may account for the conflicting results in different studies. Epidemiologic studies consisted mostly of newly postmenopausal women and those who were being treated for symptoms of vasomotor instability. In contrast, the Women’s Health Initiative enrolled only women older than 65 and excluded women with vasomotor instability. Other studies indicate that the greatest cognitive improvements with hormone therapies are seen in women with vasomotor symptoms.

WHICH RISK FACTORS CAN WE CONTROL?

In summary, some of the risk factors for Alzheimer disease can be modified if we do the following.

Aggressively manage diabetes and cardiovascular disease. Vascular risk factors significantly increase dementia risk, providing good targets for prevention: clinicians should aggressively help their patients control diabetes, hypertension, and hyperlipidemia.²⁶ However, aggressive control of hypertension in a patient with already-existing dementia may exacerbate the condition, so caution is warranted.

Optimize diet. Dietary measures include high intake of antioxidants (which are especially high in brightly colored and tart-flavored fruits and vegetables) and polyunsaturated fats.²⁶ Eating a Mediterranean-type diet that includes a high intake of cold-water ocean fish is recommended. Fish should not be fried: the high temperatures may destroy the omega-3 fatty acids, and the high fat content may inhibit their absorption.

Weigh the risks and benefits of estrogen. Although estrogen replacement therapy for postmenopausal women has had mixed results for controlling dementia, it appears to be clinically indicated to control vasomotor symptoms and likely does not increase the risk of dementia for newly menopausal women. Risks and benefits should be carefully weighed for each patient.

Optimize exercise. People who are physically active in midlife have a lower risk of Alzheimer disease.²⁷ Those who adopt new physical activity late in life may also gain some protective or restorative benefit.²⁸

Many measures, such as taking anti-inflammatory or antihypertensive drugs, probably have a very small incremental benefit over time, so it is difficult to measure significant effects during the course of a typical clinical trial.

Clinicians are already recommending actions to reduce the risk of dementia by focusing on lowering cardiovascular risk. Hopefully, as these actions become more commonly practiced as lifelong habits in those reaching the age of risk for Alzheimer disease, we will see a reduced incidence of that devastating and much-feared illness.

Reperfusion therapy decreases morbidity and mortality rates in patients with ST-segment elevation myocardial infarction (MI). Primary percutaneous coronary intervention (PCI) is preferred over fibrinolytic therapy as a reperfusion strategy when the delay in the time to treatment is short and the patient presents to a high-volume, well-equipped center with expert interventional cardiologists.

See related article

Compared with fibrinolytic therapy in randomized clinical trials, primary PCI produces higher rates of infarct artery patency, complete reperfusion (grade 3 by the criteria of the Thrombolysis in Myocardial Infarction [TIMI] study), and access-site bleeding. It also produces lower rates of recurrent ischemia, reinfarction, emergency repeat revascularization procedures, intracranial hemorrhage, and death.¹ If performed early and successfully, primary PCI also greatly decreases the rates of complications of ST-elevation MI that result from longer ischemic times or unsuccessful fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities. Primary PCI is also the best reperfusion option in patients who present late after the onset of symptoms and in patients with cardiogenic shock, and it is the only option in patients who have contraindications to fibrinolytic therapy because of bleeding risk.

However, most hospitals do not have PCI capability. Two options at these hospitals are to transfer the patient to a PCI center quickly for primary PCI or to keep the patient on site and give fibrinolytic therapy, with its limitations. Earlier trials suggested that the transfer strategy was superior, but they had limitations: most patients received streptokinase, an inferior fibrinolytic agent, and door-to-door-to-balloon times were rapid, averaging only 95 minutes because of excellent logistical protocols and careful patient selection.² Most importantly, rescue PCI and routine PCI were seldom performed in patients receiving fibrinolytics, so fibrinolytic therapy was being tested as monotherapy.

In the real world, however, treatment delays are much longer, and fibrinolytic therapy has evolved into a strategy that includes crossover to rescue PCI or routine PCI. Therefore, the initial trials of transfer for primary PCI do not reflect current practice. In fact, recent registry data suggest that prehospital fibrinolytic therapy followed by early angiography is superior to primary PCI because most patients can be treated within 2 hours of symptom onset; they also suggest that on-site fibrinolytic therapy followed by early angiography is equal in efficacy to primary PCI as long as rescue PCI and routine PCI can be performed.^3,4

The most important modifiable predictor of outcome in ST-elevation MI is the time to treatment, a biological truth that continues to be supported by clinical evidence despite ideologic arguments by some interventional cardiology enthusiasts who claim that primary PCI is always superior to the fibrinolytic strategy, regardless of delays.

SURPRISINGLY, OUTCOMES WERE WORSE WITH FACILITATED PCI

It made sense, then, to conclude that the perfect strategy for hospitals without PCI capability would be a combined strategy of immediate fibrinolytic therapy to decrease the time delay associated with organizing PCI, and rapid transfer for immediate PCI to improve the limited reperfusion rates associated with fibrinolytic therapy.

Surprisingly, though, randomized trials found worse outcomes with this “facilitated PCI” strategy.⁵

Again, limitations in trial design might explain the lack of benefit in the trials. Inadequate anticoagulant and antiplatelet therapy were given to the fibrinolytic patients, and primary PCI patients had relatively short treatment delays, with many patients enrolled at hospitals with PCI capability.

PROGRESS IN REPERFUSION THERAPY

Great strides have been made in reperfusion therapy in recent years. Adjunctive therapy with clopidogrel (Plavix) and enoxaparin (Lovenox) has been shown to improve outcomes with fibrinolytic therapy. Bivalirudin (Angiomax) and stents have improved primary PCI’s performance. Reducing bleeding complications has become a clinical priority, with increasing emphasis on adjusting some drug doses according to renal function and using the radial artery for cardiac catheterization.

The American College of Cardiology initiative, “Door-to-Balloon (D2B): An Alliance for Quality,” focused much attention on organizing in-hospital systems of care for primary PCI, thus increasing the national rate of achieving a door-to-balloon time within 90 minutes from 50% to over 75% in patients who presented to hospitals with PCI capability.⁶

The American Heart Association has launched “Mission: Lifeline,” a national campaign to organize prehospital systems of care with their program,⁷ working within communities to address their unique needs, resources, and barriers to implementing systems of care for ST-elevation MI. The key aspect of this effort is to help geographic regions develop local solutions, an explicit recognition that there is no one-size-fits-all solution. Early triage by emergency medical services, rapid diagnosis with prehospital electrocardiography, destination and interhospital transfer protocols, and prehospital activation of the cardiac catheterization laboratory can greatly streamline emergency care and decrease treatment delays for primary PCI.

FOR OUTLYING HOSPITALS, A PHARMACOINVASIVE STRATEGY

So what about hospitals without PCI capability that cannot routinely transfer patients to a hospital with PCI capability within 90 minutes?

Lessons learned from the experiences with immediate PCI, rescue PCI, and facilitated PCI have evolved into the “pharmacoinvasive strategy.” Patients with ST-elevation MI are treated as rapidly as possible with a bolus of a fibrinolytic drug, eg, tenecteplase (TNKase) or reteplase (Retavase), and are also given aspirin, clopidogrel, and enoxaparin. Then, they are rapidly transferred to a PCI-capable hospital so that emergency PCI can be performed if reperfusion is not clinically apparent or if the patient develops pulmonary edema or cardiogenic shock. If the clinical signs suggest that reperfusion has been achieved (relief of chest pain, rapid resolution of ST-segment elevation, bursts of accelerated idioventricular rhythm), coronary angiography (and PCI, if indicated) can be performed within 3 to 24 hours of fibrinolytic therapy. This time frame allows the initial fibrinolytic effect to dissipate, while the antiplatelet and anticoagulant drugs achieve therapeutic levels.

Today, the goal is to treat every patient with the best reperfusion strategy available, given the limitations in resources and the geographic location of some centers, and to maximize the possibility of sustained patency of the infarct-related artery by implanting a stent, even if it takes several hours and transfer to another hospital to perform PCI.⁸ The pharmacoinvasive strategy of rapid administration of fibrinolytic therapy followed by PCI within 24 hours would be practical in most hospitals without PCI capability where treatment delays prohibit performance of primary PCI within 90 minutes of first medical contact.⁹

THE ‘STREAM’ TRIAL IS UNDER WAY

As proof of concept, the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial is enrolling 2,000 patients with ST-elevation MI presenting within 3 hours of symptom onset if primary PCI is not feasible within 60 minutes of first medical contact.¹⁰ Patients will be randomized to either of the following:

• Receive prehospital therapy with tenecteplase, aspirin, clopidogrel, and enoxaparin and undergo cardiac catheterization in 6 to 24 hours (or rescue PCI if reperfusion fails within 90 minutes of fibrinolysis)
• Undergo primary PCI performed according to local guidelines.

The primary measure of efficacy will be the composite rate of death, cardiogenic shock, heart failure, and reinfarction at 30 days. Measures of safety include the rates of ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding.

Reperfusion therapy decreases morbidity and mortality rates in patients with ST-segment elevation myocardial infarction (MI). Primary percutaneous coronary intervention (PCI) is preferred over fibrinolytic therapy as a reperfusion strategy when the delay in the time to treatment is short and the patient presents to a high-volume, well-equipped center with expert interventional cardiologists.

See related article

Compared with fibrinolytic therapy in randomized clinical trials, primary PCI produces higher rates of infarct artery patency, complete reperfusion (grade 3 by the criteria of the Thrombolysis in Myocardial Infarction [TIMI] study), and access-site bleeding. It also produces lower rates of recurrent ischemia, reinfarction, emergency repeat revascularization procedures, intracranial hemorrhage, and death.¹ If performed early and successfully, primary PCI also greatly decreases the rates of complications of ST-elevation MI that result from longer ischemic times or unsuccessful fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities. Primary PCI is also the best reperfusion option in patients who present late after the onset of symptoms and in patients with cardiogenic shock, and it is the only option in patients who have contraindications to fibrinolytic therapy because of bleeding risk.

However, most hospitals do not have PCI capability. Two options at these hospitals are to transfer the patient to a PCI center quickly for primary PCI or to keep the patient on site and give fibrinolytic therapy, with its limitations. Earlier trials suggested that the transfer strategy was superior, but they had limitations: most patients received streptokinase, an inferior fibrinolytic agent, and door-to-door-to-balloon times were rapid, averaging only 95 minutes because of excellent logistical protocols and careful patient selection.² Most importantly, rescue PCI and routine PCI were seldom performed in patients receiving fibrinolytics, so fibrinolytic therapy was being tested as monotherapy.

In the real world, however, treatment delays are much longer, and fibrinolytic therapy has evolved into a strategy that includes crossover to rescue PCI or routine PCI. Therefore, the initial trials of transfer for primary PCI do not reflect current practice. In fact, recent registry data suggest that prehospital fibrinolytic therapy followed by early angiography is superior to primary PCI because most patients can be treated within 2 hours of symptom onset; they also suggest that on-site fibrinolytic therapy followed by early angiography is equal in efficacy to primary PCI as long as rescue PCI and routine PCI can be performed.^3,4

The most important modifiable predictor of outcome in ST-elevation MI is the time to treatment, a biological truth that continues to be supported by clinical evidence despite ideologic arguments by some interventional cardiology enthusiasts who claim that primary PCI is always superior to the fibrinolytic strategy, regardless of delays.

SURPRISINGLY, OUTCOMES WERE WORSE WITH FACILITATED PCI

It made sense, then, to conclude that the perfect strategy for hospitals without PCI capability would be a combined strategy of immediate fibrinolytic therapy to decrease the time delay associated with organizing PCI, and rapid transfer for immediate PCI to improve the limited reperfusion rates associated with fibrinolytic therapy.

Surprisingly, though, randomized trials found worse outcomes with this “facilitated PCI” strategy.⁵

Again, limitations in trial design might explain the lack of benefit in the trials. Inadequate anticoagulant and antiplatelet therapy were given to the fibrinolytic patients, and primary PCI patients had relatively short treatment delays, with many patients enrolled at hospitals with PCI capability.

PROGRESS IN REPERFUSION THERAPY

Great strides have been made in reperfusion therapy in recent years. Adjunctive therapy with clopidogrel (Plavix) and enoxaparin (Lovenox) has been shown to improve outcomes with fibrinolytic therapy. Bivalirudin (Angiomax) and stents have improved primary PCI’s performance. Reducing bleeding complications has become a clinical priority, with increasing emphasis on adjusting some drug doses according to renal function and using the radial artery for cardiac catheterization.

The American College of Cardiology initiative, “Door-to-Balloon (D2B): An Alliance for Quality,” focused much attention on organizing in-hospital systems of care for primary PCI, thus increasing the national rate of achieving a door-to-balloon time within 90 minutes from 50% to over 75% in patients who presented to hospitals with PCI capability.⁶

The American Heart Association has launched “Mission: Lifeline,” a national campaign to organize prehospital systems of care with their program,⁷ working within communities to address their unique needs, resources, and barriers to implementing systems of care for ST-elevation MI. The key aspect of this effort is to help geographic regions develop local solutions, an explicit recognition that there is no one-size-fits-all solution. Early triage by emergency medical services, rapid diagnosis with prehospital electrocardiography, destination and interhospital transfer protocols, and prehospital activation of the cardiac catheterization laboratory can greatly streamline emergency care and decrease treatment delays for primary PCI.

FOR OUTLYING HOSPITALS, A PHARMACOINVASIVE STRATEGY

So what about hospitals without PCI capability that cannot routinely transfer patients to a hospital with PCI capability within 90 minutes?

Lessons learned from the experiences with immediate PCI, rescue PCI, and facilitated PCI have evolved into the “pharmacoinvasive strategy.” Patients with ST-elevation MI are treated as rapidly as possible with a bolus of a fibrinolytic drug, eg, tenecteplase (TNKase) or reteplase (Retavase), and are also given aspirin, clopidogrel, and enoxaparin. Then, they are rapidly transferred to a PCI-capable hospital so that emergency PCI can be performed if reperfusion is not clinically apparent or if the patient develops pulmonary edema or cardiogenic shock. If the clinical signs suggest that reperfusion has been achieved (relief of chest pain, rapid resolution of ST-segment elevation, bursts of accelerated idioventricular rhythm), coronary angiography (and PCI, if indicated) can be performed within 3 to 24 hours of fibrinolytic therapy. This time frame allows the initial fibrinolytic effect to dissipate, while the antiplatelet and anticoagulant drugs achieve therapeutic levels.

Today, the goal is to treat every patient with the best reperfusion strategy available, given the limitations in resources and the geographic location of some centers, and to maximize the possibility of sustained patency of the infarct-related artery by implanting a stent, even if it takes several hours and transfer to another hospital to perform PCI.⁸ The pharmacoinvasive strategy of rapid administration of fibrinolytic therapy followed by PCI within 24 hours would be practical in most hospitals without PCI capability where treatment delays prohibit performance of primary PCI within 90 minutes of first medical contact.⁹

THE ‘STREAM’ TRIAL IS UNDER WAY

As proof of concept, the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial is enrolling 2,000 patients with ST-elevation MI presenting within 3 hours of symptom onset if primary PCI is not feasible within 60 minutes of first medical contact.¹⁰ Patients will be randomized to either of the following:

• Receive prehospital therapy with tenecteplase, aspirin, clopidogrel, and enoxaparin and undergo cardiac catheterization in 6 to 24 hours (or rescue PCI if reperfusion fails within 90 minutes of fibrinolysis)
• Undergo primary PCI performed according to local guidelines.

The primary measure of efficacy will be the composite rate of death, cardiogenic shock, heart failure, and reinfarction at 30 days. Measures of safety include the rates of ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding.

Reperfusion therapy decreases morbidity and mortality rates in patients with ST-segment elevation myocardial infarction (MI). Primary percutaneous coronary intervention (PCI) is preferred over fibrinolytic therapy as a reperfusion strategy when the delay in the time to treatment is short and the patient presents to a high-volume, well-equipped center with expert interventional cardiologists.

See related article

Compared with fibrinolytic therapy in randomized clinical trials, primary PCI produces higher rates of infarct artery patency, complete reperfusion (grade 3 by the criteria of the Thrombolysis in Myocardial Infarction [TIMI] study), and access-site bleeding. It also produces lower rates of recurrent ischemia, reinfarction, emergency repeat revascularization procedures, intracranial hemorrhage, and death.¹ If performed early and successfully, primary PCI also greatly decreases the rates of complications of ST-elevation MI that result from longer ischemic times or unsuccessful fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities. Primary PCI is also the best reperfusion option in patients who present late after the onset of symptoms and in patients with cardiogenic shock, and it is the only option in patients who have contraindications to fibrinolytic therapy because of bleeding risk.

However, most hospitals do not have PCI capability. Two options at these hospitals are to transfer the patient to a PCI center quickly for primary PCI or to keep the patient on site and give fibrinolytic therapy, with its limitations. Earlier trials suggested that the transfer strategy was superior, but they had limitations: most patients received streptokinase, an inferior fibrinolytic agent, and door-to-door-to-balloon times were rapid, averaging only 95 minutes because of excellent logistical protocols and careful patient selection.² Most importantly, rescue PCI and routine PCI were seldom performed in patients receiving fibrinolytics, so fibrinolytic therapy was being tested as monotherapy.

In the real world, however, treatment delays are much longer, and fibrinolytic therapy has evolved into a strategy that includes crossover to rescue PCI or routine PCI. Therefore, the initial trials of transfer for primary PCI do not reflect current practice. In fact, recent registry data suggest that prehospital fibrinolytic therapy followed by early angiography is superior to primary PCI because most patients can be treated within 2 hours of symptom onset; they also suggest that on-site fibrinolytic therapy followed by early angiography is equal in efficacy to primary PCI as long as rescue PCI and routine PCI can be performed.^3,4

The most important modifiable predictor of outcome in ST-elevation MI is the time to treatment, a biological truth that continues to be supported by clinical evidence despite ideologic arguments by some interventional cardiology enthusiasts who claim that primary PCI is always superior to the fibrinolytic strategy, regardless of delays.

SURPRISINGLY, OUTCOMES WERE WORSE WITH FACILITATED PCI

It made sense, then, to conclude that the perfect strategy for hospitals without PCI capability would be a combined strategy of immediate fibrinolytic therapy to decrease the time delay associated with organizing PCI, and rapid transfer for immediate PCI to improve the limited reperfusion rates associated with fibrinolytic therapy.

Surprisingly, though, randomized trials found worse outcomes with this “facilitated PCI” strategy.⁵

Again, limitations in trial design might explain the lack of benefit in the trials. Inadequate anticoagulant and antiplatelet therapy were given to the fibrinolytic patients, and primary PCI patients had relatively short treatment delays, with many patients enrolled at hospitals with PCI capability.

PROGRESS IN REPERFUSION THERAPY

Great strides have been made in reperfusion therapy in recent years. Adjunctive therapy with clopidogrel (Plavix) and enoxaparin (Lovenox) has been shown to improve outcomes with fibrinolytic therapy. Bivalirudin (Angiomax) and stents have improved primary PCI’s performance. Reducing bleeding complications has become a clinical priority, with increasing emphasis on adjusting some drug doses according to renal function and using the radial artery for cardiac catheterization.

The American College of Cardiology initiative, “Door-to-Balloon (D2B): An Alliance for Quality,” focused much attention on organizing in-hospital systems of care for primary PCI, thus increasing the national rate of achieving a door-to-balloon time within 90 minutes from 50% to over 75% in patients who presented to hospitals with PCI capability.⁶

The American Heart Association has launched “Mission: Lifeline,” a national campaign to organize prehospital systems of care with their program,⁷ working within communities to address their unique needs, resources, and barriers to implementing systems of care for ST-elevation MI. The key aspect of this effort is to help geographic regions develop local solutions, an explicit recognition that there is no one-size-fits-all solution. Early triage by emergency medical services, rapid diagnosis with prehospital electrocardiography, destination and interhospital transfer protocols, and prehospital activation of the cardiac catheterization laboratory can greatly streamline emergency care and decrease treatment delays for primary PCI.

FOR OUTLYING HOSPITALS, A PHARMACOINVASIVE STRATEGY

So what about hospitals without PCI capability that cannot routinely transfer patients to a hospital with PCI capability within 90 minutes?

Lessons learned from the experiences with immediate PCI, rescue PCI, and facilitated PCI have evolved into the “pharmacoinvasive strategy.” Patients with ST-elevation MI are treated as rapidly as possible with a bolus of a fibrinolytic drug, eg, tenecteplase (TNKase) or reteplase (Retavase), and are also given aspirin, clopidogrel, and enoxaparin. Then, they are rapidly transferred to a PCI-capable hospital so that emergency PCI can be performed if reperfusion is not clinically apparent or if the patient develops pulmonary edema or cardiogenic shock. If the clinical signs suggest that reperfusion has been achieved (relief of chest pain, rapid resolution of ST-segment elevation, bursts of accelerated idioventricular rhythm), coronary angiography (and PCI, if indicated) can be performed within 3 to 24 hours of fibrinolytic therapy. This time frame allows the initial fibrinolytic effect to dissipate, while the antiplatelet and anticoagulant drugs achieve therapeutic levels.

Today, the goal is to treat every patient with the best reperfusion strategy available, given the limitations in resources and the geographic location of some centers, and to maximize the possibility of sustained patency of the infarct-related artery by implanting a stent, even if it takes several hours and transfer to another hospital to perform PCI.⁸ The pharmacoinvasive strategy of rapid administration of fibrinolytic therapy followed by PCI within 24 hours would be practical in most hospitals without PCI capability where treatment delays prohibit performance of primary PCI within 90 minutes of first medical contact.⁹

THE ‘STREAM’ TRIAL IS UNDER WAY

As proof of concept, the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial is enrolling 2,000 patients with ST-elevation MI presenting within 3 hours of symptom onset if primary PCI is not feasible within 60 minutes of first medical contact.¹⁰ Patients will be randomized to either of the following:

• Receive prehospital therapy with tenecteplase, aspirin, clopidogrel, and enoxaparin and undergo cardiac catheterization in 6 to 24 hours (or rescue PCI if reperfusion fails within 90 minutes of fibrinolysis)
• Undergo primary PCI performed according to local guidelines.

The primary measure of efficacy will be the composite rate of death, cardiogenic shock, heart failure, and reinfarction at 30 days. Measures of safety include the rates of ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding.

Effective and rapid reperfusion is crucial in patients with acute ST-segment elevation myocardial infarction (MI). The preferred strategy for reperfusion—when it can be performed in a timely fashion at an experienced facility—is primary percutaneous coronary intervention (PCI), which produces outcomes superior to those of pharmacologic thrombolysis.¹

See related editorial

Unfortunately, in the United States about half of patients present to hospitals that do not have PCI capability,² and in one analysis, 91% of transferred patients had a door-to-balloon time greater than the recommended 90 minutes, with a mean of 152 minutes.³ (In this case, the door-to-balloon time was the time that elapsed between entry into the first hospital and inflation of the PCI balloon at the second hospital.)

In situations such as these, a combined approach may be appropriate, with thrombolysis delivered by paramedics or at a local facility, followed by transfer to a PCI facility and performance of PCI within a few hours. However, this is feasible only if standardized community-based or regional protocols for prompt transfer and reperfusion are in place.

In this paper we discuss the rationale and the clinical data behind several approaches to combined reperfusion, as well as experiences with community-based care protocols.

WITHIN 3 HOURS OF SYMPTOM ONSET, THROMBOLYSIS IS AS GOOD AS PCI

The PRAGUE-2 Trial

In the randomized PRAGUE-2 trial,⁴ patients with ST-elevation MI who presented to a non-PCI facility had better outcomes if they were transferred promptly for PCI (median door-to-balloon time 97 minutes), as opposed to receiving local therapy with streptokinase. However, for patients presenting within 3 hours of symptom onset, the mortality rates were comparable with either strategy.⁴

See the glossary of clinical trial names below

The CAPTIM trial

In the CAPTIM trial,⁵ patients who presented within 2 hours of symptom onset and who were randomized to receive prehospital thrombolysis had outcomes similar to those of patients treated with primary PCI, despite a short door-to-balloon time (82 minutes).

The Vienna STEMI Registry

In the Vienna STEMI Registry,⁶ the mortality rates with primary PCI and with thrombolysis were similar when patients presented within 2 hours of symptom onset. However, as the time from symptom onset increased, primary PCI appeared to offer an increasing survival benefit compared with thrombolysis.

Comments: Thrombolysis is effective mostly in the first 2 to 3 hours, with some benefit up to 12 hours

Previous studies have shown that the sooner thrombolysis is given after symptom onset, the more effective it is. If it is given within an hour of symptom onset, the relative reduction in the mortality rate is 50% and the absolute reduction is 6.5% compared with no reperfusion therapy. If it is started in the second hour, the absolute reduction in the mortality rate drops to 4%, and a lesser benefit extends to patients presenting up to 12 hours after symptom onset.⁷ This time-dependent benefit is due to the fact that very early reperfusion of the occluded coronary artery may lead to full recovery of ischemic tissue and thus prevent necrosis. In addition, thrombolysis in the first 2 hours is highly efficacious in lysing a fresh thrombus.

These data support the current guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA), which state no preference for either thrombolytic therapy or PCI in ST-elevation MI if the presentation is less than 3 hours after symptom onset.⁸

Of note, in the CAPTIM trial and in the Vienna STEMI Registry, rescue PCI was available and was in fact used after thrombolysis in about 25% of patients, which might have contributed to the benefit of early thrombolysis.

PRIMARY PCI MAY NOT BE SUPERIOR IF TRANSFER TIME IS LONG

Another time-related factor to consider is the PCI-related delay, ie, the theoretical difference between the expected time from first medical contact to balloon inflation (if the patient undergoes primary PCI) and the time from first medical contact to the start of thrombolytic therapy (if the patient undergoes primary thrombolysis).

A meta-analysis of 13 trials comparing PCI and thrombolysis showed that a PCI-related delay of more than 60 minutes might negate the potential advantage of primary PCI over immediate thrombolysis in terms of deaths.⁹

This observation has been further refined by data from the National Registry of Myocardial Infarction.¹⁰ In this analysis, patient factors, including age, duration of symptoms, and infarct location, significantly affected the point at which the PCI-related delay negated the survival advantage of primary PCI. The survival advantage of primary PCI was lost more rapidly—with a PCI-related delay as short as 40 minutes—in patients who presented sooner, were younger, or had anterior MI. Primary PCI maintained its survival advantage even with a PCI-related delay longer than 100 minutes in older patients or patients with nonanterior MI presenting more than 3 hours after symptom onset. Given that median door-to-balloon times in the United States may exceed 150 minutes when transfer is involved, ³ primary PCI may be no better than primary thrombolysis in transferred patients who present early or who have large infarcts.

Although these results were derived from a post hoc analysis of a registry and the delay times reported were sometimes inaccurate, they suggest that both the PCI-related delay time and patient characteristics should be considered when selecting a reperfusion strategy. Thrombolytic therapy before and in conjunction with primary PCI was considered a potential solution to these concerns.

In addition, while the benefit of any reperfusion strategy depends on the time of presentation, the loss in benefit by later presentation is less pronounced with primary PCI than with thrombolysis, making thrombolysis less attractive in later presentations (> 3 hours).¹¹

Also, while thrombolytic therapy in patients older than 75 years was associated with a lower mortality rate compared with no therapy in a large Swedish registry,¹² this benefit was less striking than in younger patients. A meta-analysis of thrombolysis trials failed to show a similar benefit in patients over age 75 vs younger patients,¹³ whereas primary PCI remained effective and superior to thrombolysis in the elderly, with more absolute reduction in mortality rates in the elderly subgroup than with younger patients. ¹⁴ This makes thrombolysis less attractive in the elderly, either as a stand-alone therapy or in conjunction with PCI. Studies of combined thrombolysis and PCI included very few patients over age 75.^15–17

THREE COMBINATION REPERFUSION STRATEGIES

Facilitated PCI is a strategy of thrombolysis immediately followed by PCI, with a planned door-to-balloon time of 90 to 120 minutes.

Pharmacoinvasive therapy means giving thrombolysis at a non-PCI facility and then promptly and systematically transferring the patient to a PCI facility, where PCI is performed 2 to 24 hours after the start of thrombolytic therapy, regardless of whether thrombolysis results in successful reperfusion. ¹⁵ Thus, the time to PCI is longer than with facilitated PCI. Facilitated PCI addresses the value of pretreatment with thrombolytics or glycoprotein IIb/IIIa inhibitors in patients otherwise eligible for primary PCI, whereas pharmacoinvasive therapy addresses the value of routine early PCI after thrombolysis in patients who are not eligible for primary PCI.¹⁶

Rescue PCI refers to PCI that is performed urgently if thrombolysis fails, failure being defined as persistent hemodynamic or electrical instability, persistent ischemic symptoms, or failure to achieve at least a 50% to 70% resolution of the maximal ST-segment elevation 90 minutes after the infusion is started.

FACILITATED PCI: NEGATIVE RESULTS IN CLINICAL TRIALS

ASSENT-4 PCI trial

In the ASSENT-4 PCI trial,¹⁸ patients receiving full thrombolytic therapy before PCI had a higher rate of in-hospital death, bleeding, and cardiovascular events at 90 days than patients treated with primary PCI.

This trial recruited patients arriving at hospitals with or without PCI capability. The door-to-balloon time was about 110 minutes in both groups, which might not have been prolonged enough to show a benefit from a timely addition of thrombolysis. In addition, antiplatelet therapy was limited in these patients: glycoprotein IIb/IIIa inhibitors were not given, and clopidogrel (Plavix) was not appropriately preloaded, and this might have offset the potential benefit of early PCI. In fact, data suggest that platelet activation and aggregation are heightened after thrombolysis, ^21–23 and that glycoprotein IIb/IIIa antagonists can inhibit these effects.²³

The FINESSE trial

In the FINESSE trial,¹⁹ patients were randomized to undergo primary PCI, to undergo PCI facilitated (ie, preceded) by abciximab (Reo-Pro), or to undergo PCI facilitated by half-dose reteplase (Retavase) and full-dose abciximab. Despite a median door-to-balloon time of 132 minutes, the three strategies were associated with similar rates of death, heart failure, or ischemic outcome at 90 days. Even though the dosage of heparin was weight-adjusted, more major bleeding events occurred with the facilitated strategies.

Comments: Some subgroups may still benefit from facilitated PCI

The results of ASSENT-4 PCI and FINESSE led to the conclusion that PCI facilitated by full-dose thrombolysis should be avoided, and called into question the value of PCI facilitation using glycoprotein IIb/IIIa inhibitors with or without half-dose thrombolytic therapy.

However, subgroup analyses of these trials identified some subgroups that may benefit from a facilitated strategy. In ASSENT-4 PCI, 45% of patients were enrolled at PCI hospitals with a minimal PCI-related delay time. These patients had the worst outcome with the facilitated strategy. In contrast, patients who had a short time from pain onset to thrombolysis (2 to 3 hours) and who were given prehospital thrombolysis had a trend toward better outcomes with facilitated PCI.²⁴ And in FINESSE, 60% of patients were enrolled at centers with PCI capability. Analysis of a small subgroup of patients with a Thrombolysis in Myocardial Infarction study (TIMI) risk score of 3 or greater presenting to non-PCI hospitals within 4 hours of symptom onset suggested a potential reduction of ischemic events with the facilitated strategy in these patients.²⁵

Thus, for patients seen in the first 2 to 3 hours after symptom onset, immediate thrombolysis is recommended if PCI will likely be delayed, with or without plans for subsequent early PCI. “Time is muscle,” especially during the first 3 hours.

PHARMACOINVASIVE STRATEGY: GOOD RESULTS IN HIGH-RISK PATIENTS

A number of randomized studies during the last 10 years have examined the value of a pharmacoinvasive strategy.^{15,16,26–29}

The TRANSFER-AMI trial

The TRANSFER-AMI trial¹⁵ randomized 1,059 patients with high-risk ST-elevation MI (ie, anterior or high-risk inferior) at non-PCI centers to undergo either pharmacoinvasive care, ie, full-dose tenecteplase (TNKase) with immediate transfer for PCI or standard care, ie, tenecteplase with transfer for rescue PCI if the patient had persistent ST-segment elevation, chest pain, or hemodynamic instability.¹⁵ The goal was to perform PCI within 6 hours of thrombolysis, and the median time to PCI was 3.9 hours (range 2–6 hours). In the standard-care group, 35% of patients needed to be transferred for rescue PCI. Unlike in the ASSENT-4 trial, over 80% of patients received aggressive antiplatelet therapy with both 300 mg of clopidogrel and glycoprotein IIb/IIIa inhibitors.

The rate of cardiovascular events at 30 days was significantly lower with pharmacoinvasive therapy than with standard care and rescue PCI (11% vs 17%, P = .004). This difference was driven by lower rates of recurrent ischemia, reinfarction, and heart failure.

The CARESS-in-AMI study

The CARESS-in-AMI study¹⁶ found a similar improvement in ischemic outcomes in 600 patients with high-risk ST-elevation MI arriving at non-PCI centers if they had received pharmacoinvasive therapy. Patients received half-dose reteplase and abciximab and were randomized either to be immediately transferred for PCI (median time to PCI 2.25 hours) or to be transferred only if they had persistent ST-segment elevation or clinical deterioration.¹⁶ The event rate was low with pharmacoinvasive therapy, comparable to that achieved in primary PCI trials.

Interestingly, no significant increase was seen in the risk of major and minor bleeding in these two trials despite the use of a femoral approach for PCI in over 80% of the cases; this is probably due to the delays between thrombolytic administration and PCI and to the use of a highly fibrin-specific thrombolytic agent and adjusted-dose heparin.

Meta-analysis of pharmacoinvasive trials

A meta-analysis²⁹ of studies of systematic early PCI (mainly with stenting) within 24 hours of thrombolysis showed a reduction in the rates of mortality and reinfarction with this strategy, without an increase in the risk of major or intracranial bleeding.³⁰ In contrast to the results of the trials of facilitated PCI, a pharmacoinvasive strategy improved outcomes in these trials because the delay between thrombolysis and PCI was more than 2 hours, ie, long enough to prevent bleeding complications, and because most patients randomized in these trials presented within 2 to 3 hours of symptom onset, when the time to reperfusion is critical. After 3 hours, the PCI-mediated myocardial salvage is less time-dependent. Moreover, trials of pharmacoinvasive strategy used aggressive antiplatelet therapy with clopidogrel and glycoprotein IIb/IIIa inhibitors.

Comment: Pharmacoinvasive strategy in the guidelines

These results and those of the subgroup analysis from the FINESSE trial suggest that patients with high-risk ST-elevation MI treated at non-PCI hospitals have better outcomes without an increase in major bleeding events when given thrombolysis and then immediately transferred for routine PCI, rather than being transferred only if reperfusion fails.

Hence, the 2009 update of the ACC/AHA guidelines³¹ gives a class IIa recommendation for transferring patients with anterior ST-elevation MI or high-risk inferior ST-elevation MI treated with thrombolysis to a PCI-capable facility where PCI is performed as part of a pharmacoinvasive or rescue strategy soon after thrombolysis.

This strategy has been particularly studied in patients younger than 75 years presenting with high-risk types of ST-elevation MI early (< 3 hours) after symptom onset. If not at high risk, the patient may be transferred to a PCI facility after receiving thrombolysis or observed in the initial facility (class IIb recommendation). Consideration should be given to starting anticoagulant and antiplatelet therapy before and during transfer—ie, 300 mg of clopidogrel before transfer for PCI and glycoprotein IIb/IIIa inhibitor therapy during PCI.

The European Society of Cardiology (ESC) guidelines³² recommend early routine angiography 3 to 24 hours after successful thrombolysis. This time window was selected to avoid PCI during the prothrombotic period in the first few hours after thrombolysis and to minimize the risk of reocclusion with PCI delays of more than 24 hours (class IIa recommendation).

Larger randomized trials are still needed to establish whether the pharmacoinvasive strategy confers a survival benefit, to determine its usefulness in low-risk inferior or lateral ST-elevation MI, and to further refine the time window when PCI is both safe and beneficial after thrombolysis.³³

RESCUE PCI REDUCES MORTALITY RATES

Rescue PCI is the most accepted form of thrombolysis-PCI combination.

The REACT trial

The REACT trial²⁰ showed that rescue PCI performed at a mean of 4.5 hours after failed thrombolysis reduces the rate of adverse cardiovascular events by more than 50% at 6 to 12 months and reduces the 5-year mortality rate by more than 50% compared with conservative management.²⁰ As in the pharmacoinvasive strategy, aggressive antiplatelet regimens were used in the REACT trial.

A meta-analysis of rescue PCI trials

A meta-analysis of rescue PCI trials³⁴ confirmed these results, showing a reduction in heart failure and reinfarction and a trend toward a lower mortality rate with rescue PCI.³⁴ After thrombolysis, 40% of patients do not achieve grade 3 TIMI flow, which explains why in modern clinical trials 30% of patients treated with thrombolysis require rescue PCI.^5,15,16,35

For patients with high-risk ST-elevation MI, current ACC/AHA guidelines assign a class IIa recommendation to rescue PCI.³¹

WHEN PATIENTS WITH ST-ELEVATION MI PRESENT TO A NON-PCI HOSPITAL

Transfer for primary PCI vs thrombolysis at the non-PCI hospital

The DANAMI-2 trial³⁶ found that immediate transfer for PCI was superior to onsite thrombolytic therapy, as measured by a reduction in the rate of ischemic events (composite of death, myocardial infarction, or stroke at 30 days): 8.5% vs 14.2% (P < .001). There were no deaths during transfer.³

The PRAGUE-2 trial⁴ showed similar results for patients presenting 3 to 12 hours after symptom onset (30-day mortality rate 6% with immediate transfer vs 15.3% with on-site thrombolysis, P < .002), whereas patients presenting within 3 hours of symptom onset had a similar mortality rate with either therapy.⁴

Comment. These trials showed that transfer for primary PCI is superior to thrombolytic therapy when performed in a timely fashion. However, they were done in countries with established transfer networks and short distances between community hospitals and PCI centers, with a PCI-related delay of only 44 minutes and a door-to-balloon time of 90 minutes despite transfer. The large-scale application of this prompt transfer policy is not practical in most regions in the United States. Thus, a strategy of local thrombolysis followed by routine early transfer for routine or rescue PCI seems warranted when the door-to-balloon time or the PCI-related delay time is expected to be too long.

Experiences with community-based systems of care and prehospital thrombolysis

In Minnesota, Henry et al³⁷ developed a PCI-based treatment system and an integrated transfer program for ST-elevation MI involving 30 hospitals within 210 miles of the Minneapolis Heart Institute. Participating hospitals were divided into two zones: zone 1 hospitals were within 60 miles, and zone 2 facilities were between 60 and 210 miles from the Heart Institute. Zone 2 patients received half-dose tenecteplase (if thrombolytic therapy was not contraindicated) in anticipation of a lengthy transfer time.

The median door-to-balloon time for zone 1 patients was 95 minutes (interquartile range 82 and 116 minutes) and for zone 2 patients 120 minutes (interquartile range 100 and 145 minutes). The diagnosis of ST-elevation MI was made by the emergency department physician, who activated the system with a phone call. The patient was then directly transferred to the catheterization laboratory, most often by helicopter.

The in-hospital death rate for patients who presented to the PCI center and for patients in zones 1 and 2 was similarly low (about 5%).³⁷

In France, the FAST-MI registry,¹⁷ which collected outcome data for different reperfusion strategies, found that thrombolysis yielded in-hospital and midterm results that were comparable to those of primary PCI. Of note, thrombolysis was started early after symptom onset (about 2 hours), and was started in the ambulance in two-thirds of cases. Nearly all patients underwent a pharmacoinvasive strategy that combined thrombolysis with coronary angiography and PCI within 24 hours of symptom onset. These findings suggest that timely thrombolysis followed by semiurgent transfer for PCI is an alternative to primary PCI for patients presenting to hospitals with no PCI capability, and that this alternative offers similar benefit to that of primary PCI.

Five centers in the United States have reported their experience with half-dose thrombolysis in the prehospital setting (in the field or during transfer) or at a non-PCI hospital, followed by prompt transfer to a PCI facility. In this registry of almost 3,000 patients,³⁸ patients treated with thrombolysis had better outcomes than patients directly transferred for primary PCI, with a significantly lower 30-day mortality rate (3.8% vs from 6.4%), and no increase in bleeding.^38,39 The mean door-to-balloon time was long (168 minutes in the primary PCI group and 196 minutes in the thrombolysis-PCI group), which might explain the benefit achieved with prompt thrombolysis.

CARDIOGENIC SHOCK

Patients presenting with left ventricular cardiogenic shock derive a large mortality benefit from revascularization, whether they are transferred or directly admitted to a PCI center. ⁴⁰ Moreover, in the SHOCK registry, patients with predominant right ventricular cardiogenic shock had an in-hospital mortality rate similar to that of patients with predominant left ventricular cardiogenic shock, and revascularization (PCI or surgical revascularization) was associated with a strikingly lower mortality rate in both groups.⁴¹

Thus, all patients with left or right cardiogenic shock should be revascularized on an emergency basis, either surgically or percutaneously.

While trials of pharmacoinvasive therapy excluded patients with cardiogenic shock,^15,16 thrombolytic therapy was associated with improved outcomes in the drug-therapy group of the SHOCK trial and in hypotensive patients randomized in the early thrombolysis trials.¹³ Thus, the ACC/AHA guidelines recommend thrombolytic therapy before transfer if a patient presents in shock within 3 to 6 hours of onset of the MI and delays in transport and intervention are anticipated.⁸

PUTTING IT ALL TOGETHER: MANAGEMENT STRATEGIES

If an effective transfer system is in place, primary PCI not preceded by thrombolytic therapy or glycoprotein IIb/IIIa inhibitor therapy is the preferred approach, according to ACC/AHA and ESC guidelines.^31,32 Giving thrombolytics immediately before PCI is harmful and thus should be avoided when the expected door-to-balloon time is 90 minutes or less.

All hospitals (whether or not they offer PCI) and regional emergency medical services should participate in a community-based system of care for ST-elevation MI, with protocols for expeditious transfer as defined and coordinated by the American Heart Association initiative “Mission: Lifeline.” In addition, a system of field triage and direct transport to the catheterization laboratory of a PCI facility after field activation significantly reduces door-to-balloon times and improves outcomes.⁴²

If such a system is not in place, then a pharmacoinvasive strategy seems best: ie, local full-dose thrombolysis (if not contraindicated) followed by transfer to a PCI facility and routine performance of PCI 2 to 6 hours after thrombolysis—in conjunction with aggressive early dual oral antiplatelet therapy and “downstream” glycoprotein IIb/IIIa inhibition. This approach is associated with outcomes similar to those of primary PCI.^15–17,37

Prehospital thrombolysis delivered by paramedics and followed by early transfer to a PCI facility has been associated with further reduction in mortality rates compared with in-hospital thrombolysis (as in the Swedish registry⁴³), and a reduction in death rate comparable to that of primary PCI in patients presenting early. This is an adequate strategy in regions where such a system can be established.^{5,17,38,43,44}

Patients presenting more than 3 to 4 hours after symptom onset, older patients, and patients with lower-risk MI or a higher risk of bleeding may still be suited for primary PCI even when the door-to-balloon time is 90 to 120 minutes, as stated by the European guidelines,³² or when the PCI-related delay time is as long as 100 minutes. ¹⁰ On the other hand, while the ACC/AHA guidelines recognize that in these patients the mortality advantage of primary PCI vs thrombolytic therapy is maintained with more prolonged door-to-balloon times, they nevertheless state that the focus should be on developing systems of care to increase the number of patients with access to primary PCI in less than 90 minutes rather than extending the acceptable window for door-to-balloon time.

In conclusion, for patients presenting with ST-elevation MI who cannot undergo timely primary PCI, the best approach seems to be prehospital thrombolysis delivered by paramedics or local thrombolysis at the non-PCI hospital followed by transferring the patient and performing PCI within a few hours. This is especially important in patients with high-risk ST-elevation MI who present early after symptom onset, when the extent of myocardial necrosis associated with delayed primary PCI is largest.

In addition, every community should develop a coordinated transfer strategy between non-PCI and PCI hospitals.

Effective and rapid reperfusion is crucial in patients with acute ST-segment elevation myocardial infarction (MI). The preferred strategy for reperfusion—when it can be performed in a timely fashion at an experienced facility—is primary percutaneous coronary intervention (PCI), which produces outcomes superior to those of pharmacologic thrombolysis.¹

See related editorial

Unfortunately, in the United States about half of patients present to hospitals that do not have PCI capability,² and in one analysis, 91% of transferred patients had a door-to-balloon time greater than the recommended 90 minutes, with a mean of 152 minutes.³ (In this case, the door-to-balloon time was the time that elapsed between entry into the first hospital and inflation of the PCI balloon at the second hospital.)

In situations such as these, a combined approach may be appropriate, with thrombolysis delivered by paramedics or at a local facility, followed by transfer to a PCI facility and performance of PCI within a few hours. However, this is feasible only if standardized community-based or regional protocols for prompt transfer and reperfusion are in place.

In this paper we discuss the rationale and the clinical data behind several approaches to combined reperfusion, as well as experiences with community-based care protocols.

WITHIN 3 HOURS OF SYMPTOM ONSET, THROMBOLYSIS IS AS GOOD AS PCI

The PRAGUE-2 Trial

In the randomized PRAGUE-2 trial,⁴ patients with ST-elevation MI who presented to a non-PCI facility had better outcomes if they were transferred promptly for PCI (median door-to-balloon time 97 minutes), as opposed to receiving local therapy with streptokinase. However, for patients presenting within 3 hours of symptom onset, the mortality rates were comparable with either strategy.⁴

See the glossary of clinical trial names below

The CAPTIM trial

In the CAPTIM trial,⁵ patients who presented within 2 hours of symptom onset and who were randomized to receive prehospital thrombolysis had outcomes similar to those of patients treated with primary PCI, despite a short door-to-balloon time (82 minutes).

The Vienna STEMI Registry

In the Vienna STEMI Registry,⁶ the mortality rates with primary PCI and with thrombolysis were similar when patients presented within 2 hours of symptom onset. However, as the time from symptom onset increased, primary PCI appeared to offer an increasing survival benefit compared with thrombolysis.

Comments: Thrombolysis is effective mostly in the first 2 to 3 hours, with some benefit up to 12 hours

Previous studies have shown that the sooner thrombolysis is given after symptom onset, the more effective it is. If it is given within an hour of symptom onset, the relative reduction in the mortality rate is 50% and the absolute reduction is 6.5% compared with no reperfusion therapy. If it is started in the second hour, the absolute reduction in the mortality rate drops to 4%, and a lesser benefit extends to patients presenting up to 12 hours after symptom onset.⁷ This time-dependent benefit is due to the fact that very early reperfusion of the occluded coronary artery may lead to full recovery of ischemic tissue and thus prevent necrosis. In addition, thrombolysis in the first 2 hours is highly efficacious in lysing a fresh thrombus.

These data support the current guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA), which state no preference for either thrombolytic therapy or PCI in ST-elevation MI if the presentation is less than 3 hours after symptom onset.⁸

Of note, in the CAPTIM trial and in the Vienna STEMI Registry, rescue PCI was available and was in fact used after thrombolysis in about 25% of patients, which might have contributed to the benefit of early thrombolysis.

PRIMARY PCI MAY NOT BE SUPERIOR IF TRANSFER TIME IS LONG

Another time-related factor to consider is the PCI-related delay, ie, the theoretical difference between the expected time from first medical contact to balloon inflation (if the patient undergoes primary PCI) and the time from first medical contact to the start of thrombolytic therapy (if the patient undergoes primary thrombolysis).

A meta-analysis of 13 trials comparing PCI and thrombolysis showed that a PCI-related delay of more than 60 minutes might negate the potential advantage of primary PCI over immediate thrombolysis in terms of deaths.⁹

This observation has been further refined by data from the National Registry of Myocardial Infarction.¹⁰ In this analysis, patient factors, including age, duration of symptoms, and infarct location, significantly affected the point at which the PCI-related delay negated the survival advantage of primary PCI. The survival advantage of primary PCI was lost more rapidly—with a PCI-related delay as short as 40 minutes—in patients who presented sooner, were younger, or had anterior MI. Primary PCI maintained its survival advantage even with a PCI-related delay longer than 100 minutes in older patients or patients with nonanterior MI presenting more than 3 hours after symptom onset. Given that median door-to-balloon times in the United States may exceed 150 minutes when transfer is involved, ³ primary PCI may be no better than primary thrombolysis in transferred patients who present early or who have large infarcts.

Although these results were derived from a post hoc analysis of a registry and the delay times reported were sometimes inaccurate, they suggest that both the PCI-related delay time and patient characteristics should be considered when selecting a reperfusion strategy. Thrombolytic therapy before and in conjunction with primary PCI was considered a potential solution to these concerns.

In addition, while the benefit of any reperfusion strategy depends on the time of presentation, the loss in benefit by later presentation is less pronounced with primary PCI than with thrombolysis, making thrombolysis less attractive in later presentations (> 3 hours).¹¹

Also, while thrombolytic therapy in patients older than 75 years was associated with a lower mortality rate compared with no therapy in a large Swedish registry,¹² this benefit was less striking than in younger patients. A meta-analysis of thrombolysis trials failed to show a similar benefit in patients over age 75 vs younger patients,¹³ whereas primary PCI remained effective and superior to thrombolysis in the elderly, with more absolute reduction in mortality rates in the elderly subgroup than with younger patients. ¹⁴ This makes thrombolysis less attractive in the elderly, either as a stand-alone therapy or in conjunction with PCI. Studies of combined thrombolysis and PCI included very few patients over age 75.^15–17

THREE COMBINATION REPERFUSION STRATEGIES

Facilitated PCI is a strategy of thrombolysis immediately followed by PCI, with a planned door-to-balloon time of 90 to 120 minutes.

Pharmacoinvasive therapy means giving thrombolysis at a non-PCI facility and then promptly and systematically transferring the patient to a PCI facility, where PCI is performed 2 to 24 hours after the start of thrombolytic therapy, regardless of whether thrombolysis results in successful reperfusion. ¹⁵ Thus, the time to PCI is longer than with facilitated PCI. Facilitated PCI addresses the value of pretreatment with thrombolytics or glycoprotein IIb/IIIa inhibitors in patients otherwise eligible for primary PCI, whereas pharmacoinvasive therapy addresses the value of routine early PCI after thrombolysis in patients who are not eligible for primary PCI.¹⁶

Rescue PCI refers to PCI that is performed urgently if thrombolysis fails, failure being defined as persistent hemodynamic or electrical instability, persistent ischemic symptoms, or failure to achieve at least a 50% to 70% resolution of the maximal ST-segment elevation 90 minutes after the infusion is started.

FACILITATED PCI: NEGATIVE RESULTS IN CLINICAL TRIALS

ASSENT-4 PCI trial

In the ASSENT-4 PCI trial,¹⁸ patients receiving full thrombolytic therapy before PCI had a higher rate of in-hospital death, bleeding, and cardiovascular events at 90 days than patients treated with primary PCI.

This trial recruited patients arriving at hospitals with or without PCI capability. The door-to-balloon time was about 110 minutes in both groups, which might not have been prolonged enough to show a benefit from a timely addition of thrombolysis. In addition, antiplatelet therapy was limited in these patients: glycoprotein IIb/IIIa inhibitors were not given, and clopidogrel (Plavix) was not appropriately preloaded, and this might have offset the potential benefit of early PCI. In fact, data suggest that platelet activation and aggregation are heightened after thrombolysis, ^21–23 and that glycoprotein IIb/IIIa antagonists can inhibit these effects.²³

The FINESSE trial

In the FINESSE trial,¹⁹ patients were randomized to undergo primary PCI, to undergo PCI facilitated (ie, preceded) by abciximab (Reo-Pro), or to undergo PCI facilitated by half-dose reteplase (Retavase) and full-dose abciximab. Despite a median door-to-balloon time of 132 minutes, the three strategies were associated with similar rates of death, heart failure, or ischemic outcome at 90 days. Even though the dosage of heparin was weight-adjusted, more major bleeding events occurred with the facilitated strategies.

Comments: Some subgroups may still benefit from facilitated PCI

The results of ASSENT-4 PCI and FINESSE led to the conclusion that PCI facilitated by full-dose thrombolysis should be avoided, and called into question the value of PCI facilitation using glycoprotein IIb/IIIa inhibitors with or without half-dose thrombolytic therapy.

However, subgroup analyses of these trials identified some subgroups that may benefit from a facilitated strategy. In ASSENT-4 PCI, 45% of patients were enrolled at PCI hospitals with a minimal PCI-related delay time. These patients had the worst outcome with the facilitated strategy. In contrast, patients who had a short time from pain onset to thrombolysis (2 to 3 hours) and who were given prehospital thrombolysis had a trend toward better outcomes with facilitated PCI.²⁴ And in FINESSE, 60% of patients were enrolled at centers with PCI capability. Analysis of a small subgroup of patients with a Thrombolysis in Myocardial Infarction study (TIMI) risk score of 3 or greater presenting to non-PCI hospitals within 4 hours of symptom onset suggested a potential reduction of ischemic events with the facilitated strategy in these patients.²⁵

Thus, for patients seen in the first 2 to 3 hours after symptom onset, immediate thrombolysis is recommended if PCI will likely be delayed, with or without plans for subsequent early PCI. “Time is muscle,” especially during the first 3 hours.

PHARMACOINVASIVE STRATEGY: GOOD RESULTS IN HIGH-RISK PATIENTS

A number of randomized studies during the last 10 years have examined the value of a pharmacoinvasive strategy.^{15,16,26–29}

The TRANSFER-AMI trial

The TRANSFER-AMI trial¹⁵ randomized 1,059 patients with high-risk ST-elevation MI (ie, anterior or high-risk inferior) at non-PCI centers to undergo either pharmacoinvasive care, ie, full-dose tenecteplase (TNKase) with immediate transfer for PCI or standard care, ie, tenecteplase with transfer for rescue PCI if the patient had persistent ST-segment elevation, chest pain, or hemodynamic instability.¹⁵ The goal was to perform PCI within 6 hours of thrombolysis, and the median time to PCI was 3.9 hours (range 2–6 hours). In the standard-care group, 35% of patients needed to be transferred for rescue PCI. Unlike in the ASSENT-4 trial, over 80% of patients received aggressive antiplatelet therapy with both 300 mg of clopidogrel and glycoprotein IIb/IIIa inhibitors.

The rate of cardiovascular events at 30 days was significantly lower with pharmacoinvasive therapy than with standard care and rescue PCI (11% vs 17%, P = .004). This difference was driven by lower rates of recurrent ischemia, reinfarction, and heart failure.

The CARESS-in-AMI study

The CARESS-in-AMI study¹⁶ found a similar improvement in ischemic outcomes in 600 patients with high-risk ST-elevation MI arriving at non-PCI centers if they had received pharmacoinvasive therapy. Patients received half-dose reteplase and abciximab and were randomized either to be immediately transferred for PCI (median time to PCI 2.25 hours) or to be transferred only if they had persistent ST-segment elevation or clinical deterioration.¹⁶ The event rate was low with pharmacoinvasive therapy, comparable to that achieved in primary PCI trials.

Interestingly, no significant increase was seen in the risk of major and minor bleeding in these two trials despite the use of a femoral approach for PCI in over 80% of the cases; this is probably due to the delays between thrombolytic administration and PCI and to the use of a highly fibrin-specific thrombolytic agent and adjusted-dose heparin.

Meta-analysis of pharmacoinvasive trials

A meta-analysis²⁹ of studies of systematic early PCI (mainly with stenting) within 24 hours of thrombolysis showed a reduction in the rates of mortality and reinfarction with this strategy, without an increase in the risk of major or intracranial bleeding.³⁰ In contrast to the results of the trials of facilitated PCI, a pharmacoinvasive strategy improved outcomes in these trials because the delay between thrombolysis and PCI was more than 2 hours, ie, long enough to prevent bleeding complications, and because most patients randomized in these trials presented within 2 to 3 hours of symptom onset, when the time to reperfusion is critical. After 3 hours, the PCI-mediated myocardial salvage is less time-dependent. Moreover, trials of pharmacoinvasive strategy used aggressive antiplatelet therapy with clopidogrel and glycoprotein IIb/IIIa inhibitors.

Comment: Pharmacoinvasive strategy in the guidelines

These results and those of the subgroup analysis from the FINESSE trial suggest that patients with high-risk ST-elevation MI treated at non-PCI hospitals have better outcomes without an increase in major bleeding events when given thrombolysis and then immediately transferred for routine PCI, rather than being transferred only if reperfusion fails.

Hence, the 2009 update of the ACC/AHA guidelines³¹ gives a class IIa recommendation for transferring patients with anterior ST-elevation MI or high-risk inferior ST-elevation MI treated with thrombolysis to a PCI-capable facility where PCI is performed as part of a pharmacoinvasive or rescue strategy soon after thrombolysis.

This strategy has been particularly studied in patients younger than 75 years presenting with high-risk types of ST-elevation MI early (< 3 hours) after symptom onset. If not at high risk, the patient may be transferred to a PCI facility after receiving thrombolysis or observed in the initial facility (class IIb recommendation). Consideration should be given to starting anticoagulant and antiplatelet therapy before and during transfer—ie, 300 mg of clopidogrel before transfer for PCI and glycoprotein IIb/IIIa inhibitor therapy during PCI.

The European Society of Cardiology (ESC) guidelines³² recommend early routine angiography 3 to 24 hours after successful thrombolysis. This time window was selected to avoid PCI during the prothrombotic period in the first few hours after thrombolysis and to minimize the risk of reocclusion with PCI delays of more than 24 hours (class IIa recommendation).

Larger randomized trials are still needed to establish whether the pharmacoinvasive strategy confers a survival benefit, to determine its usefulness in low-risk inferior or lateral ST-elevation MI, and to further refine the time window when PCI is both safe and beneficial after thrombolysis.³³

RESCUE PCI REDUCES MORTALITY RATES

Rescue PCI is the most accepted form of thrombolysis-PCI combination.

The REACT trial

The REACT trial²⁰ showed that rescue PCI performed at a mean of 4.5 hours after failed thrombolysis reduces the rate of adverse cardiovascular events by more than 50% at 6 to 12 months and reduces the 5-year mortality rate by more than 50% compared with conservative management.²⁰ As in the pharmacoinvasive strategy, aggressive antiplatelet regimens were used in the REACT trial.

A meta-analysis of rescue PCI trials

A meta-analysis of rescue PCI trials³⁴ confirmed these results, showing a reduction in heart failure and reinfarction and a trend toward a lower mortality rate with rescue PCI.³⁴ After thrombolysis, 40% of patients do not achieve grade 3 TIMI flow, which explains why in modern clinical trials 30% of patients treated with thrombolysis require rescue PCI.^5,15,16,35

For patients with high-risk ST-elevation MI, current ACC/AHA guidelines assign a class IIa recommendation to rescue PCI.³¹

WHEN PATIENTS WITH ST-ELEVATION MI PRESENT TO A NON-PCI HOSPITAL

Transfer for primary PCI vs thrombolysis at the non-PCI hospital

The DANAMI-2 trial³⁶ found that immediate transfer for PCI was superior to onsite thrombolytic therapy, as measured by a reduction in the rate of ischemic events (composite of death, myocardial infarction, or stroke at 30 days): 8.5% vs 14.2% (P < .001). There were no deaths during transfer.³

The PRAGUE-2 trial⁴ showed similar results for patients presenting 3 to 12 hours after symptom onset (30-day mortality rate 6% with immediate transfer vs 15.3% with on-site thrombolysis, P < .002), whereas patients presenting within 3 hours of symptom onset had a similar mortality rate with either therapy.⁴

Comment. These trials showed that transfer for primary PCI is superior to thrombolytic therapy when performed in a timely fashion. However, they were done in countries with established transfer networks and short distances between community hospitals and PCI centers, with a PCI-related delay of only 44 minutes and a door-to-balloon time of 90 minutes despite transfer. The large-scale application of this prompt transfer policy is not practical in most regions in the United States. Thus, a strategy of local thrombolysis followed by routine early transfer for routine or rescue PCI seems warranted when the door-to-balloon time or the PCI-related delay time is expected to be too long.

Experiences with community-based systems of care and prehospital thrombolysis

In Minnesota, Henry et al³⁷ developed a PCI-based treatment system and an integrated transfer program for ST-elevation MI involving 30 hospitals within 210 miles of the Minneapolis Heart Institute. Participating hospitals were divided into two zones: zone 1 hospitals were within 60 miles, and zone 2 facilities were between 60 and 210 miles from the Heart Institute. Zone 2 patients received half-dose tenecteplase (if thrombolytic therapy was not contraindicated) in anticipation of a lengthy transfer time.

The median door-to-balloon time for zone 1 patients was 95 minutes (interquartile range 82 and 116 minutes) and for zone 2 patients 120 minutes (interquartile range 100 and 145 minutes). The diagnosis of ST-elevation MI was made by the emergency department physician, who activated the system with a phone call. The patient was then directly transferred to the catheterization laboratory, most often by helicopter.

The in-hospital death rate for patients who presented to the PCI center and for patients in zones 1 and 2 was similarly low (about 5%).³⁷

In France, the FAST-MI registry,¹⁷ which collected outcome data for different reperfusion strategies, found that thrombolysis yielded in-hospital and midterm results that were comparable to those of primary PCI. Of note, thrombolysis was started early after symptom onset (about 2 hours), and was started in the ambulance in two-thirds of cases. Nearly all patients underwent a pharmacoinvasive strategy that combined thrombolysis with coronary angiography and PCI within 24 hours of symptom onset. These findings suggest that timely thrombolysis followed by semiurgent transfer for PCI is an alternative to primary PCI for patients presenting to hospitals with no PCI capability, and that this alternative offers similar benefit to that of primary PCI.

Five centers in the United States have reported their experience with half-dose thrombolysis in the prehospital setting (in the field or during transfer) or at a non-PCI hospital, followed by prompt transfer to a PCI facility. In this registry of almost 3,000 patients,³⁸ patients treated with thrombolysis had better outcomes than patients directly transferred for primary PCI, with a significantly lower 30-day mortality rate (3.8% vs from 6.4%), and no increase in bleeding.^38,39 The mean door-to-balloon time was long (168 minutes in the primary PCI group and 196 minutes in the thrombolysis-PCI group), which might explain the benefit achieved with prompt thrombolysis.

CARDIOGENIC SHOCK

Patients presenting with left ventricular cardiogenic shock derive a large mortality benefit from revascularization, whether they are transferred or directly admitted to a PCI center. ⁴⁰ Moreover, in the SHOCK registry, patients with predominant right ventricular cardiogenic shock had an in-hospital mortality rate similar to that of patients with predominant left ventricular cardiogenic shock, and revascularization (PCI or surgical revascularization) was associated with a strikingly lower mortality rate in both groups.⁴¹

Thus, all patients with left or right cardiogenic shock should be revascularized on an emergency basis, either surgically or percutaneously.

While trials of pharmacoinvasive therapy excluded patients with cardiogenic shock,^15,16 thrombolytic therapy was associated with improved outcomes in the drug-therapy group of the SHOCK trial and in hypotensive patients randomized in the early thrombolysis trials.¹³ Thus, the ACC/AHA guidelines recommend thrombolytic therapy before transfer if a patient presents in shock within 3 to 6 hours of onset of the MI and delays in transport and intervention are anticipated.⁸

PUTTING IT ALL TOGETHER: MANAGEMENT STRATEGIES

If an effective transfer system is in place, primary PCI not preceded by thrombolytic therapy or glycoprotein IIb/IIIa inhibitor therapy is the preferred approach, according to ACC/AHA and ESC guidelines.^31,32 Giving thrombolytics immediately before PCI is harmful and thus should be avoided when the expected door-to-balloon time is 90 minutes or less.

All hospitals (whether or not they offer PCI) and regional emergency medical services should participate in a community-based system of care for ST-elevation MI, with protocols for expeditious transfer as defined and coordinated by the American Heart Association initiative “Mission: Lifeline.” In addition, a system of field triage and direct transport to the catheterization laboratory of a PCI facility after field activation significantly reduces door-to-balloon times and improves outcomes.⁴²

If such a system is not in place, then a pharmacoinvasive strategy seems best: ie, local full-dose thrombolysis (if not contraindicated) followed by transfer to a PCI facility and routine performance of PCI 2 to 6 hours after thrombolysis—in conjunction with aggressive early dual oral antiplatelet therapy and “downstream” glycoprotein IIb/IIIa inhibition. This approach is associated with outcomes similar to those of primary PCI.^15–17,37

Prehospital thrombolysis delivered by paramedics and followed by early transfer to a PCI facility has been associated with further reduction in mortality rates compared with in-hospital thrombolysis (as in the Swedish registry⁴³), and a reduction in death rate comparable to that of primary PCI in patients presenting early. This is an adequate strategy in regions where such a system can be established.^{5,17,38,43,44}

Patients presenting more than 3 to 4 hours after symptom onset, older patients, and patients with lower-risk MI or a higher risk of bleeding may still be suited for primary PCI even when the door-to-balloon time is 90 to 120 minutes, as stated by the European guidelines,³² or when the PCI-related delay time is as long as 100 minutes. ¹⁰ On the other hand, while the ACC/AHA guidelines recognize that in these patients the mortality advantage of primary PCI vs thrombolytic therapy is maintained with more prolonged door-to-balloon times, they nevertheless state that the focus should be on developing systems of care to increase the number of patients with access to primary PCI in less than 90 minutes rather than extending the acceptable window for door-to-balloon time.

In conclusion, for patients presenting with ST-elevation MI who cannot undergo timely primary PCI, the best approach seems to be prehospital thrombolysis delivered by paramedics or local thrombolysis at the non-PCI hospital followed by transferring the patient and performing PCI within a few hours. This is especially important in patients with high-risk ST-elevation MI who present early after symptom onset, when the extent of myocardial necrosis associated with delayed primary PCI is largest.

In addition, every community should develop a coordinated transfer strategy between non-PCI and PCI hospitals.

Effective and rapid reperfusion is crucial in patients with acute ST-segment elevation myocardial infarction (MI). The preferred strategy for reperfusion—when it can be performed in a timely fashion at an experienced facility—is primary percutaneous coronary intervention (PCI), which produces outcomes superior to those of pharmacologic thrombolysis.¹

See related editorial

Unfortunately, in the United States about half of patients present to hospitals that do not have PCI capability,² and in one analysis, 91% of transferred patients had a door-to-balloon time greater than the recommended 90 minutes, with a mean of 152 minutes.³ (In this case, the door-to-balloon time was the time that elapsed between entry into the first hospital and inflation of the PCI balloon at the second hospital.)

In situations such as these, a combined approach may be appropriate, with thrombolysis delivered by paramedics or at a local facility, followed by transfer to a PCI facility and performance of PCI within a few hours. However, this is feasible only if standardized community-based or regional protocols for prompt transfer and reperfusion are in place.

In this paper we discuss the rationale and the clinical data behind several approaches to combined reperfusion, as well as experiences with community-based care protocols.

WITHIN 3 HOURS OF SYMPTOM ONSET, THROMBOLYSIS IS AS GOOD AS PCI

The PRAGUE-2 Trial

In the randomized PRAGUE-2 trial,⁴ patients with ST-elevation MI who presented to a non-PCI facility had better outcomes if they were transferred promptly for PCI (median door-to-balloon time 97 minutes), as opposed to receiving local therapy with streptokinase. However, for patients presenting within 3 hours of symptom onset, the mortality rates were comparable with either strategy.⁴

See the glossary of clinical trial names below

The CAPTIM trial

In the CAPTIM trial,⁵ patients who presented within 2 hours of symptom onset and who were randomized to receive prehospital thrombolysis had outcomes similar to those of patients treated with primary PCI, despite a short door-to-balloon time (82 minutes).

The Vienna STEMI Registry

In the Vienna STEMI Registry,⁶ the mortality rates with primary PCI and with thrombolysis were similar when patients presented within 2 hours of symptom onset. However, as the time from symptom onset increased, primary PCI appeared to offer an increasing survival benefit compared with thrombolysis.

Comments: Thrombolysis is effective mostly in the first 2 to 3 hours, with some benefit up to 12 hours

Previous studies have shown that the sooner thrombolysis is given after symptom onset, the more effective it is. If it is given within an hour of symptom onset, the relative reduction in the mortality rate is 50% and the absolute reduction is 6.5% compared with no reperfusion therapy. If it is started in the second hour, the absolute reduction in the mortality rate drops to 4%, and a lesser benefit extends to patients presenting up to 12 hours after symptom onset.⁷ This time-dependent benefit is due to the fact that very early reperfusion of the occluded coronary artery may lead to full recovery of ischemic tissue and thus prevent necrosis. In addition, thrombolysis in the first 2 hours is highly efficacious in lysing a fresh thrombus.

These data support the current guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA), which state no preference for either thrombolytic therapy or PCI in ST-elevation MI if the presentation is less than 3 hours after symptom onset.⁸

Of note, in the CAPTIM trial and in the Vienna STEMI Registry, rescue PCI was available and was in fact used after thrombolysis in about 25% of patients, which might have contributed to the benefit of early thrombolysis.

PRIMARY PCI MAY NOT BE SUPERIOR IF TRANSFER TIME IS LONG

Another time-related factor to consider is the PCI-related delay, ie, the theoretical difference between the expected time from first medical contact to balloon inflation (if the patient undergoes primary PCI) and the time from first medical contact to the start of thrombolytic therapy (if the patient undergoes primary thrombolysis).

A meta-analysis of 13 trials comparing PCI and thrombolysis showed that a PCI-related delay of more than 60 minutes might negate the potential advantage of primary PCI over immediate thrombolysis in terms of deaths.⁹

This observation has been further refined by data from the National Registry of Myocardial Infarction.¹⁰ In this analysis, patient factors, including age, duration of symptoms, and infarct location, significantly affected the point at which the PCI-related delay negated the survival advantage of primary PCI. The survival advantage of primary PCI was lost more rapidly—with a PCI-related delay as short as 40 minutes—in patients who presented sooner, were younger, or had anterior MI. Primary PCI maintained its survival advantage even with a PCI-related delay longer than 100 minutes in older patients or patients with nonanterior MI presenting more than 3 hours after symptom onset. Given that median door-to-balloon times in the United States may exceed 150 minutes when transfer is involved, ³ primary PCI may be no better than primary thrombolysis in transferred patients who present early or who have large infarcts.

Although these results were derived from a post hoc analysis of a registry and the delay times reported were sometimes inaccurate, they suggest that both the PCI-related delay time and patient characteristics should be considered when selecting a reperfusion strategy. Thrombolytic therapy before and in conjunction with primary PCI was considered a potential solution to these concerns.

In addition, while the benefit of any reperfusion strategy depends on the time of presentation, the loss in benefit by later presentation is less pronounced with primary PCI than with thrombolysis, making thrombolysis less attractive in later presentations (> 3 hours).¹¹

Also, while thrombolytic therapy in patients older than 75 years was associated with a lower mortality rate compared with no therapy in a large Swedish registry,¹² this benefit was less striking than in younger patients. A meta-analysis of thrombolysis trials failed to show a similar benefit in patients over age 75 vs younger patients,¹³ whereas primary PCI remained effective and superior to thrombolysis in the elderly, with more absolute reduction in mortality rates in the elderly subgroup than with younger patients. ¹⁴ This makes thrombolysis less attractive in the elderly, either as a stand-alone therapy or in conjunction with PCI. Studies of combined thrombolysis and PCI included very few patients over age 75.^15–17

THREE COMBINATION REPERFUSION STRATEGIES

Facilitated PCI is a strategy of thrombolysis immediately followed by PCI, with a planned door-to-balloon time of 90 to 120 minutes.

Pharmacoinvasive therapy means giving thrombolysis at a non-PCI facility and then promptly and systematically transferring the patient to a PCI facility, where PCI is performed 2 to 24 hours after the start of thrombolytic therapy, regardless of whether thrombolysis results in successful reperfusion. ¹⁵ Thus, the time to PCI is longer than with facilitated PCI. Facilitated PCI addresses the value of pretreatment with thrombolytics or glycoprotein IIb/IIIa inhibitors in patients otherwise eligible for primary PCI, whereas pharmacoinvasive therapy addresses the value of routine early PCI after thrombolysis in patients who are not eligible for primary PCI.¹⁶

Rescue PCI refers to PCI that is performed urgently if thrombolysis fails, failure being defined as persistent hemodynamic or electrical instability, persistent ischemic symptoms, or failure to achieve at least a 50% to 70% resolution of the maximal ST-segment elevation 90 minutes after the infusion is started.

FACILITATED PCI: NEGATIVE RESULTS IN CLINICAL TRIALS

ASSENT-4 PCI trial

In the ASSENT-4 PCI trial,¹⁸ patients receiving full thrombolytic therapy before PCI had a higher rate of in-hospital death, bleeding, and cardiovascular events at 90 days than patients treated with primary PCI.

This trial recruited patients arriving at hospitals with or without PCI capability. The door-to-balloon time was about 110 minutes in both groups, which might not have been prolonged enough to show a benefit from a timely addition of thrombolysis. In addition, antiplatelet therapy was limited in these patients: glycoprotein IIb/IIIa inhibitors were not given, and clopidogrel (Plavix) was not appropriately preloaded, and this might have offset the potential benefit of early PCI. In fact, data suggest that platelet activation and aggregation are heightened after thrombolysis, ^21–23 and that glycoprotein IIb/IIIa antagonists can inhibit these effects.²³

The FINESSE trial

In the FINESSE trial,¹⁹ patients were randomized to undergo primary PCI, to undergo PCI facilitated (ie, preceded) by abciximab (Reo-Pro), or to undergo PCI facilitated by half-dose reteplase (Retavase) and full-dose abciximab. Despite a median door-to-balloon time of 132 minutes, the three strategies were associated with similar rates of death, heart failure, or ischemic outcome at 90 days. Even though the dosage of heparin was weight-adjusted, more major bleeding events occurred with the facilitated strategies.

Comments: Some subgroups may still benefit from facilitated PCI

The results of ASSENT-4 PCI and FINESSE led to the conclusion that PCI facilitated by full-dose thrombolysis should be avoided, and called into question the value of PCI facilitation using glycoprotein IIb/IIIa inhibitors with or without half-dose thrombolytic therapy.

However, subgroup analyses of these trials identified some subgroups that may benefit from a facilitated strategy. In ASSENT-4 PCI, 45% of patients were enrolled at PCI hospitals with a minimal PCI-related delay time. These patients had the worst outcome with the facilitated strategy. In contrast, patients who had a short time from pain onset to thrombolysis (2 to 3 hours) and who were given prehospital thrombolysis had a trend toward better outcomes with facilitated PCI.²⁴ And in FINESSE, 60% of patients were enrolled at centers with PCI capability. Analysis of a small subgroup of patients with a Thrombolysis in Myocardial Infarction study (TIMI) risk score of 3 or greater presenting to non-PCI hospitals within 4 hours of symptom onset suggested a potential reduction of ischemic events with the facilitated strategy in these patients.²⁵

Thus, for patients seen in the first 2 to 3 hours after symptom onset, immediate thrombolysis is recommended if PCI will likely be delayed, with or without plans for subsequent early PCI. “Time is muscle,” especially during the first 3 hours.

PHARMACOINVASIVE STRATEGY: GOOD RESULTS IN HIGH-RISK PATIENTS

A number of randomized studies during the last 10 years have examined the value of a pharmacoinvasive strategy.^{15,16,26–29}

The TRANSFER-AMI trial

The TRANSFER-AMI trial¹⁵ randomized 1,059 patients with high-risk ST-elevation MI (ie, anterior or high-risk inferior) at non-PCI centers to undergo either pharmacoinvasive care, ie, full-dose tenecteplase (TNKase) with immediate transfer for PCI or standard care, ie, tenecteplase with transfer for rescue PCI if the patient had persistent ST-segment elevation, chest pain, or hemodynamic instability.¹⁵ The goal was to perform PCI within 6 hours of thrombolysis, and the median time to PCI was 3.9 hours (range 2–6 hours). In the standard-care group, 35% of patients needed to be transferred for rescue PCI. Unlike in the ASSENT-4 trial, over 80% of patients received aggressive antiplatelet therapy with both 300 mg of clopidogrel and glycoprotein IIb/IIIa inhibitors.

The rate of cardiovascular events at 30 days was significantly lower with pharmacoinvasive therapy than with standard care and rescue PCI (11% vs 17%, P = .004). This difference was driven by lower rates of recurrent ischemia, reinfarction, and heart failure.

The CARESS-in-AMI study

The CARESS-in-AMI study¹⁶ found a similar improvement in ischemic outcomes in 600 patients with high-risk ST-elevation MI arriving at non-PCI centers if they had received pharmacoinvasive therapy. Patients received half-dose reteplase and abciximab and were randomized either to be immediately transferred for PCI (median time to PCI 2.25 hours) or to be transferred only if they had persistent ST-segment elevation or clinical deterioration.¹⁶ The event rate was low with pharmacoinvasive therapy, comparable to that achieved in primary PCI trials.

Interestingly, no significant increase was seen in the risk of major and minor bleeding in these two trials despite the use of a femoral approach for PCI in over 80% of the cases; this is probably due to the delays between thrombolytic administration and PCI and to the use of a highly fibrin-specific thrombolytic agent and adjusted-dose heparin.

Meta-analysis of pharmacoinvasive trials

A meta-analysis²⁹ of studies of systematic early PCI (mainly with stenting) within 24 hours of thrombolysis showed a reduction in the rates of mortality and reinfarction with this strategy, without an increase in the risk of major or intracranial bleeding.³⁰ In contrast to the results of the trials of facilitated PCI, a pharmacoinvasive strategy improved outcomes in these trials because the delay between thrombolysis and PCI was more than 2 hours, ie, long enough to prevent bleeding complications, and because most patients randomized in these trials presented within 2 to 3 hours of symptom onset, when the time to reperfusion is critical. After 3 hours, the PCI-mediated myocardial salvage is less time-dependent. Moreover, trials of pharmacoinvasive strategy used aggressive antiplatelet therapy with clopidogrel and glycoprotein IIb/IIIa inhibitors.

Comment: Pharmacoinvasive strategy in the guidelines

These results and those of the subgroup analysis from the FINESSE trial suggest that patients with high-risk ST-elevation MI treated at non-PCI hospitals have better outcomes without an increase in major bleeding events when given thrombolysis and then immediately transferred for routine PCI, rather than being transferred only if reperfusion fails.

Hence, the 2009 update of the ACC/AHA guidelines³¹ gives a class IIa recommendation for transferring patients with anterior ST-elevation MI or high-risk inferior ST-elevation MI treated with thrombolysis to a PCI-capable facility where PCI is performed as part of a pharmacoinvasive or rescue strategy soon after thrombolysis.

This strategy has been particularly studied in patients younger than 75 years presenting with high-risk types of ST-elevation MI early (< 3 hours) after symptom onset. If not at high risk, the patient may be transferred to a PCI facility after receiving thrombolysis or observed in the initial facility (class IIb recommendation). Consideration should be given to starting anticoagulant and antiplatelet therapy before and during transfer—ie, 300 mg of clopidogrel before transfer for PCI and glycoprotein IIb/IIIa inhibitor therapy during PCI.

The European Society of Cardiology (ESC) guidelines³² recommend early routine angiography 3 to 24 hours after successful thrombolysis. This time window was selected to avoid PCI during the prothrombotic period in the first few hours after thrombolysis and to minimize the risk of reocclusion with PCI delays of more than 24 hours (class IIa recommendation).

Larger randomized trials are still needed to establish whether the pharmacoinvasive strategy confers a survival benefit, to determine its usefulness in low-risk inferior or lateral ST-elevation MI, and to further refine the time window when PCI is both safe and beneficial after thrombolysis.³³

RESCUE PCI REDUCES MORTALITY RATES

Rescue PCI is the most accepted form of thrombolysis-PCI combination.

The REACT trial

The REACT trial²⁰ showed that rescue PCI performed at a mean of 4.5 hours after failed thrombolysis reduces the rate of adverse cardiovascular events by more than 50% at 6 to 12 months and reduces the 5-year mortality rate by more than 50% compared with conservative management.²⁰ As in the pharmacoinvasive strategy, aggressive antiplatelet regimens were used in the REACT trial.

A meta-analysis of rescue PCI trials

A meta-analysis of rescue PCI trials³⁴ confirmed these results, showing a reduction in heart failure and reinfarction and a trend toward a lower mortality rate with rescue PCI.³⁴ After thrombolysis, 40% of patients do not achieve grade 3 TIMI flow, which explains why in modern clinical trials 30% of patients treated with thrombolysis require rescue PCI.^5,15,16,35

For patients with high-risk ST-elevation MI, current ACC/AHA guidelines assign a class IIa recommendation to rescue PCI.³¹

WHEN PATIENTS WITH ST-ELEVATION MI PRESENT TO A NON-PCI HOSPITAL

Transfer for primary PCI vs thrombolysis at the non-PCI hospital

The DANAMI-2 trial³⁶ found that immediate transfer for PCI was superior to onsite thrombolytic therapy, as measured by a reduction in the rate of ischemic events (composite of death, myocardial infarction, or stroke at 30 days): 8.5% vs 14.2% (P < .001). There were no deaths during transfer.³

The PRAGUE-2 trial⁴ showed similar results for patients presenting 3 to 12 hours after symptom onset (30-day mortality rate 6% with immediate transfer vs 15.3% with on-site thrombolysis, P < .002), whereas patients presenting within 3 hours of symptom onset had a similar mortality rate with either therapy.⁴

Comment. These trials showed that transfer for primary PCI is superior to thrombolytic therapy when performed in a timely fashion. However, they were done in countries with established transfer networks and short distances between community hospitals and PCI centers, with a PCI-related delay of only 44 minutes and a door-to-balloon time of 90 minutes despite transfer. The large-scale application of this prompt transfer policy is not practical in most regions in the United States. Thus, a strategy of local thrombolysis followed by routine early transfer for routine or rescue PCI seems warranted when the door-to-balloon time or the PCI-related delay time is expected to be too long.

Experiences with community-based systems of care and prehospital thrombolysis

In Minnesota, Henry et al³⁷ developed a PCI-based treatment system and an integrated transfer program for ST-elevation MI involving 30 hospitals within 210 miles of the Minneapolis Heart Institute. Participating hospitals were divided into two zones: zone 1 hospitals were within 60 miles, and zone 2 facilities were between 60 and 210 miles from the Heart Institute. Zone 2 patients received half-dose tenecteplase (if thrombolytic therapy was not contraindicated) in anticipation of a lengthy transfer time.

The median door-to-balloon time for zone 1 patients was 95 minutes (interquartile range 82 and 116 minutes) and for zone 2 patients 120 minutes (interquartile range 100 and 145 minutes). The diagnosis of ST-elevation MI was made by the emergency department physician, who activated the system with a phone call. The patient was then directly transferred to the catheterization laboratory, most often by helicopter.

The in-hospital death rate for patients who presented to the PCI center and for patients in zones 1 and 2 was similarly low (about 5%).³⁷

In France, the FAST-MI registry,¹⁷ which collected outcome data for different reperfusion strategies, found that thrombolysis yielded in-hospital and midterm results that were comparable to those of primary PCI. Of note, thrombolysis was started early after symptom onset (about 2 hours), and was started in the ambulance in two-thirds of cases. Nearly all patients underwent a pharmacoinvasive strategy that combined thrombolysis with coronary angiography and PCI within 24 hours of symptom onset. These findings suggest that timely thrombolysis followed by semiurgent transfer for PCI is an alternative to primary PCI for patients presenting to hospitals with no PCI capability, and that this alternative offers similar benefit to that of primary PCI.

Five centers in the United States have reported their experience with half-dose thrombolysis in the prehospital setting (in the field or during transfer) or at a non-PCI hospital, followed by prompt transfer to a PCI facility. In this registry of almost 3,000 patients,³⁸ patients treated with thrombolysis had better outcomes than patients directly transferred for primary PCI, with a significantly lower 30-day mortality rate (3.8% vs from 6.4%), and no increase in bleeding.^38,39 The mean door-to-balloon time was long (168 minutes in the primary PCI group and 196 minutes in the thrombolysis-PCI group), which might explain the benefit achieved with prompt thrombolysis.

CARDIOGENIC SHOCK

Patients presenting with left ventricular cardiogenic shock derive a large mortality benefit from revascularization, whether they are transferred or directly admitted to a PCI center. ⁴⁰ Moreover, in the SHOCK registry, patients with predominant right ventricular cardiogenic shock had an in-hospital mortality rate similar to that of patients with predominant left ventricular cardiogenic shock, and revascularization (PCI or surgical revascularization) was associated with a strikingly lower mortality rate in both groups.⁴¹

Thus, all patients with left or right cardiogenic shock should be revascularized on an emergency basis, either surgically or percutaneously.

While trials of pharmacoinvasive therapy excluded patients with cardiogenic shock,^15,16 thrombolytic therapy was associated with improved outcomes in the drug-therapy group of the SHOCK trial and in hypotensive patients randomized in the early thrombolysis trials.¹³ Thus, the ACC/AHA guidelines recommend thrombolytic therapy before transfer if a patient presents in shock within 3 to 6 hours of onset of the MI and delays in transport and intervention are anticipated.⁸

PUTTING IT ALL TOGETHER: MANAGEMENT STRATEGIES

If an effective transfer system is in place, primary PCI not preceded by thrombolytic therapy or glycoprotein IIb/IIIa inhibitor therapy is the preferred approach, according to ACC/AHA and ESC guidelines.^31,32 Giving thrombolytics immediately before PCI is harmful and thus should be avoided when the expected door-to-balloon time is 90 minutes or less.

All hospitals (whether or not they offer PCI) and regional emergency medical services should participate in a community-based system of care for ST-elevation MI, with protocols for expeditious transfer as defined and coordinated by the American Heart Association initiative “Mission: Lifeline.” In addition, a system of field triage and direct transport to the catheterization laboratory of a PCI facility after field activation significantly reduces door-to-balloon times and improves outcomes.⁴²

If such a system is not in place, then a pharmacoinvasive strategy seems best: ie, local full-dose thrombolysis (if not contraindicated) followed by transfer to a PCI facility and routine performance of PCI 2 to 6 hours after thrombolysis—in conjunction with aggressive early dual oral antiplatelet therapy and “downstream” glycoprotein IIb/IIIa inhibition. This approach is associated with outcomes similar to those of primary PCI.^15–17,37

Prehospital thrombolysis delivered by paramedics and followed by early transfer to a PCI facility has been associated with further reduction in mortality rates compared with in-hospital thrombolysis (as in the Swedish registry⁴³), and a reduction in death rate comparable to that of primary PCI in patients presenting early. This is an adequate strategy in regions where such a system can be established.^{5,17,38,43,44}

Patients presenting more than 3 to 4 hours after symptom onset, older patients, and patients with lower-risk MI or a higher risk of bleeding may still be suited for primary PCI even when the door-to-balloon time is 90 to 120 minutes, as stated by the European guidelines,³² or when the PCI-related delay time is as long as 100 minutes. ¹⁰ On the other hand, while the ACC/AHA guidelines recognize that in these patients the mortality advantage of primary PCI vs thrombolytic therapy is maintained with more prolonged door-to-balloon times, they nevertheless state that the focus should be on developing systems of care to increase the number of patients with access to primary PCI in less than 90 minutes rather than extending the acceptable window for door-to-balloon time.

In conclusion, for patients presenting with ST-elevation MI who cannot undergo timely primary PCI, the best approach seems to be prehospital thrombolysis delivered by paramedics or local thrombolysis at the non-PCI hospital followed by transferring the patient and performing PCI within a few hours. This is especially important in patients with high-risk ST-elevation MI who present early after symptom onset, when the extent of myocardial necrosis associated with delayed primary PCI is largest.

In addition, every community should develop a coordinated transfer strategy between non-PCI and PCI hospitals.

In subsequent years we learned about HIV—the retrovirus, and the immune system that it cleverly and efficiently disables. For the most part, we matured professionally and moved past the social stigmas of the disease, although that was painful. We developed systems to keep acutely ill patients out of the hospital while providing them with “long-term” (weeks or months of) intravenous antibiotics and humane palliative care.

We learned about AZT and argued about when to use it. But mainly, we watched many, many young men (and some women) die in corner hospital rooms. For me, from the ′80s, there remain heartrending personal images, notes, and cassette tapes voicing thanks for my concern and time spent, but no notes of thanks like those I’ve received from my patients with chronic rheumatoid arthritis who, after years of care, are able to hold their nieces or grandchildren.

A few long-term survivors have raised the hope that immune systems could recover and exist in symbiosis with the virus, and that maybe a drug cocktail or vaccine could provide a cure or remission. Magic Johnson, known to be infected since at least 1991, is likely the most public example of a long-term survivor on highly active antiviral therapy—a hope in the flesh.

But did we ever expect a time when HIV would be viewed as a chronic disease, with patients warranting screening for coronary artery disease in order to decrease long-term coronary complications? Did we ever expect a time that we would be offering organ transplants to HIV-infected patients?

In this issue of the Journal, Drs. Malvestutto and Aberg discuss coronary issues that need to be recognized and managed in HIV-infected patients. This further complicates the management of these patients, and draws cardiologists and primary care providers back into management plans.

I can’t think of a management “complication” of a chronic illness that is more welcome—or more surprising.

In subsequent years we learned about HIV—the retrovirus, and the immune system that it cleverly and efficiently disables. For the most part, we matured professionally and moved past the social stigmas of the disease, although that was painful. We developed systems to keep acutely ill patients out of the hospital while providing them with “long-term” (weeks or months of) intravenous antibiotics and humane palliative care.

We learned about AZT and argued about when to use it. But mainly, we watched many, many young men (and some women) die in corner hospital rooms. For me, from the ′80s, there remain heartrending personal images, notes, and cassette tapes voicing thanks for my concern and time spent, but no notes of thanks like those I’ve received from my patients with chronic rheumatoid arthritis who, after years of care, are able to hold their nieces or grandchildren.

A few long-term survivors have raised the hope that immune systems could recover and exist in symbiosis with the virus, and that maybe a drug cocktail or vaccine could provide a cure or remission. Magic Johnson, known to be infected since at least 1991, is likely the most public example of a long-term survivor on highly active antiviral therapy—a hope in the flesh.

But did we ever expect a time when HIV would be viewed as a chronic disease, with patients warranting screening for coronary artery disease in order to decrease long-term coronary complications? Did we ever expect a time that we would be offering organ transplants to HIV-infected patients?

In this issue of the Journal, Drs. Malvestutto and Aberg discuss coronary issues that need to be recognized and managed in HIV-infected patients. This further complicates the management of these patients, and draws cardiologists and primary care providers back into management plans.

I can’t think of a management “complication” of a chronic illness that is more welcome—or more surprising.

In subsequent years we learned about HIV—the retrovirus, and the immune system that it cleverly and efficiently disables. For the most part, we matured professionally and moved past the social stigmas of the disease, although that was painful. We developed systems to keep acutely ill patients out of the hospital while providing them with “long-term” (weeks or months of) intravenous antibiotics and humane palliative care.

We learned about AZT and argued about when to use it. But mainly, we watched many, many young men (and some women) die in corner hospital rooms. For me, from the ′80s, there remain heartrending personal images, notes, and cassette tapes voicing thanks for my concern and time spent, but no notes of thanks like those I’ve received from my patients with chronic rheumatoid arthritis who, after years of care, are able to hold their nieces or grandchildren.

A few long-term survivors have raised the hope that immune systems could recover and exist in symbiosis with the virus, and that maybe a drug cocktail or vaccine could provide a cure or remission. Magic Johnson, known to be infected since at least 1991, is likely the most public example of a long-term survivor on highly active antiviral therapy—a hope in the flesh.

But did we ever expect a time when HIV would be viewed as a chronic disease, with patients warranting screening for coronary artery disease in order to decrease long-term coronary complications? Did we ever expect a time that we would be offering organ transplants to HIV-infected patients?

In this issue of the Journal, Drs. Malvestutto and Aberg discuss coronary issues that need to be recognized and managed in HIV-infected patients. This further complicates the management of these patients, and draws cardiologists and primary care providers back into management plans.

I can’t think of a management “complication” of a chronic illness that is more welcome—or more surprising.

Widespread use of antiretroviral therapy has caused a remarkable decline in rates of morbidity and death related to acquired immunodeficiency syndrome (AIDS) and has effectively made human immunodeficiency virus (HIV) infection a manageable—although not yet curable— chronic condition. And as the HIV-infected population on antiretroviral therapy ages, the prevalence of chronic conditions (eg, cardiovascular disease, hepatic disease, pulmonary disease, non-AIDS cancers) and deaths attributable to these conditions have also increased.¹

Many of the traditional risk factors for cardiovascular disease in the general population, including smoking, dyslipidemia, and diabetes, are common in HIV-infected patients, and HIV infection itself independently increases the risk of coronary heart disease. In addition, different antiretroviral combinations can contribute, in varying degrees, to changes in lipid levels and insulin resistance, further increasing coronary risk.

Ultimately, however, the immunologic benefits of antiretroviral therapy for individual patients far exceed the modest increase in cardiovascular risk associated with certain regimens. In most cases, careful selection of the initial antiretroviral regimen and the addition of lipid-lowering or glucose-controlling medications (with close attention to drug interactions) can effectively manage the metabolic changes associated with antiretroviral therapy and obviate any premature modification of virologically suppressive regimens.

TRADITIONAL CARDIAC RISK FACTORS IN HIV PATIENTS

The risk of coronary heart disease in HIV patients is influenced mostly by traditional factors such as age, smoking, diabetes, and dyslipidemia, including high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C).²

In various large cohorts, HIV-infected men had a higher prevalence of smoking,³ a lower mean HDL-C level,^3,4 and a higher mean triglyceride level^3,4 than men without HIV infection, placing them at greater risk of coronary heart disease. However, even after adjusting for traditional risk factors, rates of atherosclerosis are still higher in people who are infected with HIV than in those who are not.⁵

EFFECT OF HIV INFECTION ON CORONARY RISK

HIV infection has been shown to increase coronary risk.

In the Kaiser Permanente database,⁶ HIV-positive patients had a significantly higher rate of hospitalizations for coronary heart disease than did people who were not infected.

Similarly, in a cohort study of almost 4,000 HIV-infected patients and more than 1 million controls, the risk of acute myocardial infarction was 75% higher for HIV-positive patients than for HIV-negative patients, even after adjusting for sex, race, hypertension, diabetes, and dyslipidemia.⁵

The Fat Redistribution and Metabolism (FRAM) cross-sectional study⁷ showed that HIV infection was associated with greater carotid intima media thickness, an established marker of atherosclerosis, independently of traditional risk factors and to virtually the same degree as smoking and male sex.

Other studies of subclinical atherosclerosis in HIV patients have yielded disparate results, likely because of differences in study design, methods of measuring carotid thickness, and characteristics of the study populations (eg, prevalence of cardiovascular risk factors and stage of HIV disease). However, a meta-analysis of six prospective cohort studies, three case-control studies, and four cross-sectional studies confirmed that HIV patients had slightly but statistically significantly greater carotid intima media thickness than HIV-negative people.⁸

MECHANISMS BY WHICH HIV MAY PROMOTE CORONARY HEART DISEASE

The pathogenesis of coronary heart disease in HIV infection has not been fully elucidated, but the virus appears to contribute directly to the accelerated development of atherosclerosis. It may do so through direct effects on cholesterol processing and transport, attraction of monocytes to the intimal wall, and activation of monocytes to induce an inflammatory response and endothelial proliferation.

Effects on lipids

In early HIV infection, levels of total cholesterol and HDL-C are lower. In more advanced infection, lower CD4+ lymphocyte counts have been associated with lower levels of apolipoprotein B and with smaller LDL-C particles, suggesting that HIV affects lipid processing and delivery to vessel walls.⁹ HIV infection is also associated with reduced clearance of LDL-C.¹⁰ HIV appears to specifically inhibit the compensatory efflux of excess cholesterol from macrophages, thus promoting the formation of foam cells in atherosclerotic plaque.¹¹

Attraction of monocytes to the vessel wall

In vitro studies also suggest that HIV enhances migration of monocytes into the vascular intima during atherosclerotic plaque development by promoting secretion of the chemokine monocyte chemoattractant protein 1¹² and the expression of endothelial cell adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin.¹³

Inflammation

A recent study suggests that chronic inflammation may be a key contributor to the accelerated development of atherosclerosis in HIV patients. Hsue et al¹⁴ compared carotid intima media thickness and levels of C-reactive protein (a marker of systemic inflammation) in HIV-positive and HIV-negative patients. The carotid intima media thickness was greater in all groups of HIV patients, irrespective of level of viremia or exposure to antiretroviral therapy, than in healthy controls. In addition, C-reactive protein levels remained elevated in HIV-infected participants regardless of their level of viremia.

These findings suggest not only that HIV-associated atherosclerosis is determined by advanced immunodeficiency, high-level viremia, and exposure to antiretroviral drugs, but also that persistent inflammation due to HIV infection may play an important role in accelerated atherosclerosis.

EFFECT OF ANTIRETROVIRAL THERAPY ON CORONARY RISK

Antiretroviral therapy is associated with a small but significant increase in coronary risk.

Medi-Cal,¹⁵ a retrospective study of 28,513 patients, found antiretroviral therapy to be associated with coronary heart disease among patients 18 to 33 years of age (relative risk 2.06, P < .001).

The Data Collection on Adverse Events of Anti-HIV Drugs study¹⁶ prospectively followed 23,437 patients for 94,469 person-years. Adjusted for exposure to nonnucleoside reverse transcriptase inhibitors and for hypertension and diabetes, the relative risk of myocardial infarction per year of protease inhibitor exposure was 1.16 (95% confidence interval [CI] 1.10–1.23). The relative risk was lower after adjusting for serum lipid levels but remained significant at 1.10 (95% CI 1.04–1.18).

Reports have been mixed regarding a possible association between myocardial infarction and the nucleoside reverse transcriptase inhibitor abacavir (Ziagen): several studies found a statistically significant association,^17–20 and others did not.^21–23 Differences in study design (observational cohort studies vs prospective randomized clinical trials), populations studied (differing in age, cardiovascular risk factor prevalence, and whether the patients had already been exposed to treatment), and outcome definition probably contributed to the different conclusions.

On the other hand, several studies have shown that suppression of HIV with antiretroviral therapy actually improves some of the surrogate markers of cardiovascular disease. For example:

• Markers of endothelial function such as flow-mediated vasodilation improve significantly within 4 weeks of a patient’s starting antiretroviral therapy, regardless of the class of antiretroviral drug used.²⁴
• After viral suppression is achieved, levels of the markers of endothelial activation VCAM-1 and P-selectin decline significantly, as do levels of the adipocyte activation marker leptin and the coagulation marker D-dimer.^25,26
• Levels of the anti-inflammatory markers adiponectin and interleukin 10 increase. ^25,26

Interrupting antiretroviral therapy may increase coronary risk

Not only is uncontrolled viral replication in untreated HIV infection associated with cardiovascular disease, but interrupting antiretroviral therapy may result in a supplementary increase in coronary risk.

In the 5,472-patient Strategies for Management of Antiretroviral Therapy (SMART) trial, the rate of cardiovascular disease events was higher if treatment was interrupted than with continuous treatment, with a hazard ratio of 1.57 (95% CI 1.0–2.46, P = .05).²⁷

This association between treatment interruption and coronary events does not appear to be related to the level of viremia.²⁸ Rather, development of cardiovascular disease in HIV-infected patients who interrupt antiretroviral therapy may be mediated, to a large extent, by chronic inflammation in the setting of viral replication. In the treatment-interruption group, levels of the inflammatory cytokine interleukin 6 (IL-6) and the coagulation marker D-dimer were significantly elevated 1 month after randomization, and these differences were strongly associated with death (odds ratio [OR] 12.6, P < .0001 for IL-6; OR 13.1, P < .0001 for D-dimer). Elevated IL-6 levels were also significantly associated with the development of cardiovascular disease (OR 2.8, P = .03).²⁹

METABOLIC COMPLICATIONS OF ANTIRETROVIRAL THERAPY

Persons with HIV infection may experience metabolic complications that are due to HIV itself or to its treatment.

Cross-sectional studies that included HIV-negative patients as controls have demonstrated changes in lipid processing that are known to promote atherosclerosis. For example, persons with HIV infection have smaller LDL-C particles³⁰ and higher levels of circulating oxidized LDL-C.³¹

In the Multicenter AIDS Cohort Study (MACS), after HIV seroconversion, nonfasting total cholesterol, LDL-C, and HDL-C levels declined, which is consistent with a chronic inflammatory state. After antiretroviral therapy was started, lipid levels returned to baseline levels or slightly higher except for HDL-C, which remained low.⁹ These changes may be due to a general “return to health,” or they may be direct medication effects.

Similar patterns were seen in the SMART study.²⁸ Participants randomized to receive intermittent antiretroviral therapy had overall decreases in all lipid levels, with a marked reduction in HDL-C, while those randomized to receive continuous therapy had increased levels of all lipids, including HDL-C, at 12 months. Overall, the ratio of total cholesterol to HDL-C actually increased for participants on episodic therapy, while it decreased in the continuous-treatment group. Along with continued vascular inflammation, the low HDL-C may have contributed to the worse cardiovascular outcomes in patients who received intermittent antiretroviral therapy.

Some lipid changes associated with antiretroviral therapy may actually be beneficial. For example, nonnucleoside reverse transcriptase inhibitors may raise HDL-C levels. However, such increases alone do not necessarily offset the other lipid changes or translate to an observed improvement in coronary risk.³²

The degree of dyslipidemia and specific lipid changes differ among the different classes of antiretroviral drugs and even among the individual drugs within each class. Furthermore, the magnitude of the observed lipid changes varies widely among patients on the same antiretroviral regimen, reflecting the likely important role of host genomics.

While the protease inhibitors and nonnucleoside reverse transcriptase inhibitors have well-described effects on lipids (described in greater detail in the following sections), there have been no reported significant changes in lipid profiles or cardiovascular risk associated with the newest classes, ie, fusion inhibitors such as enfuvirtide (Fuzeon), CC chemokine receptor type 5 (CCR5) receptor inhibitors such as maraviroc (Selzentry), or integrase inhibitors such as raltegravir (Isentress).

Ritonavir (Norvir) and ritonavir-boosted protease inhibitor combinations cause the most significant increases in lipids. Currently, ritonavir is used in low doses to boost the levels of most other protease inhibitors as the standard of care in protease inhibitor-based regimens. However, in most patients, giving ritonavir with protease inhibitors raises lipid levels, particularly triglycerides.

Most boosted protease inhibitor regimens have similar effects on lipid levels, with some exceptions.

Tipranavir (Aptivus) plus ritonavir, for example, markedly raises total cholesterol and triglyceride levels and would not be recommended for patients with dyslipidemia at baseline.³³

Atazanavir (Reyataz)^34,35 plus ritonavir and darunavir (Prezista)³⁶ plus ritonavir cause more modest lipid changes. Unboosted atazanavir raises lipid levels only minimally, if at all,^34,35 but it is no longer a preferred regimen according to US Department of Health and Human Services guidelines.⁴²

Impact of nonnucleoside reverse transcriptase inhibitors on lipids

Efavirenz (Sustiva), a nonnucleoside reverse transcriptase inhibitor, when added to a regimen of two or three nucleoside reverse transcriptase inhibitors, resulted in modest increases in all lipids, including HDL-C (a potentially beneficial change) at 96 weeks compared with a regimen of three nucleoside reverse transcriptase inhibitors only.⁴³

Nevirapine (Viramune), compared with efavirenz, results in a more favorable lipid profile in previously untreated patients, as shown by larger increases in HDL-C and smaller increases in triglycerides at 48 weeks.⁴⁴

Etravirine (Intelence), the newest nonnucleoside reverse transcriptase inhibitor, does not appear to cause any further increase in lipids when added to a regimen containing darunavir-ritonavir and nucleoside agents.⁴⁵

Impact of nucleoside reverse transcriptase inhibitors on lipids

As a class, nucleoside reverse transcriptase inhibitors have been associated with mitochondrial toxicity and insulin resistance,⁴⁶ but the lipid changes associated with them are generally less significant than those caused by protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Nevertheless, within the class, there is considerable variability in lipid changes associated with specific agents.

Stavudine (Zerit), for example, is associated with hypertriglyceridemia.

Tenofovir (Viread), for another example, in combination with emtricitabine (Emtriva) and the nonnucleoside reverse transcriptase inhibitor efavirenz (the three drugs are contained in a formulation called Atripla) was associated with a smaller increase in fasting total cholesterol than with zidovudine-lamivudine and efavirenz at 96 weeks.⁴⁷

A recent placebo-controlled, crossover, pilot study of 17 HIV-infected patients suggested that tenofovir may actually have independent lipid-lowering properties.⁴⁸

Abacavir, as discussed above, has been reported to be associated with a higher risk of myocardial infarction, but this is debatable.

MANAGING CORONARY RISK FACTORS IN HIV-INFECTED PATIENTS

Cardiovascular risk assessment

In HIV patients, cardiovascular risk can be assessed using models derived from large epidemiologic studies such as the Framingham Heart Study.⁴⁹

Current guidelines from the Infectious Diseases Society of America and the AIDS Clinical Trials Group (ACTG) for evaluating and managing dyslipidemia in HIV-infected adults are based on the National Cholesterol Education Program Adult Treatment Panel III.⁵⁰ They recommend obtaining a fasting lipid profile before starting antiretroviral therapy and within 3 to 6 months after starting a new regimen.

The guidelines also recommend stratifying risk by counting the number of cardiovascular risk factors, as is done for the general population. If the patient has more than two factors, the Framingham equation should be used to calculate the 10-year risk of myocardial infarction or cardiac death. Interventions should be offered for modifiable cardiovascular risk factors such as smoking, hypertension, physical inactivity, and diabetes mellitus. LDL-C goals should be determined, and lipid-lowering drugs should be initiated accordingly. If triglyceride levels are 200 to 500 mg/dL and levels of “non-HDL-C” (total cholesterol minus the HDL-C level) are high, a statin is recommended. If the triglyceride level is higher than 500 mg/dL, a fibrate should be started.⁵¹

In HIV patients, statin and fibrate therapy must be considered cautiously, given the important drug interactions with protease inhibitors and especially ritonavir. Many statins are metabolized by cytochrome P3A4, which protease inhibitors inhibit.

Statins generally considered safe to use with most protease inhibitors:

• Pravastatin (Pravachol)
• Rosuvastatin (Crestor)
• Atorvastatin (Lipitor).

Exceptions and caveats:

• Pravastatin should not be prescribed with boosted darunavir.
• Data for fluvastatin (Lescol) in HIV-infected patients on antiretroviral therapy are limited.
• Lovastatin (Mevacor) and simvastatin (Zocor) are contraindicated with protease inhibitor therapy.⁵²
• In contrast to the increase in statin levels seen with protease inhibitors, efavirenz lowers levels of simvastatin, pravastatin, and atorvastatin.^53,54

Ezetimibe (Zetia), which is metabolized independently of the cytochrome P450 system, has been shown to be safe and effective when given to HIV-infected patients on antiretroviral therapy.⁵⁸

Fenofibrate (Lofibra) is recommended by current guidelines for patients with elevated triglyceride levels (> 500 mg/dL).⁵¹ In the ACTG 5087 study, a combination of fenofibrate plus pravastatin was found to be safe and effective in improving lipid profiles.⁵⁹

Long-acting niacin resulted in significant improvements in triglycerides, total cholesterol, HDL-C, and LDL-C after 48 weeks of use, although insulin sensitivity worsened.⁶⁰

Fish oil has been shown to be an effective alternative to fibrates, or it can be used in combination with them.⁶¹

Switching antiretroviral agents vs adding lipid-lowering agents. In some patients with significant dyslipidemia, switching antiretro viral agents may lower lipid levels without compromising virologic control.⁶² However, due to the multifactorial nature of dyslipidemia in HIV patients on antiretroviral therapy, switching the HIV therapy alone may not result in sufficient improvement in the lipid profile⁴⁵ and may be associated with virologic failure, particularly among patients who have underlying treatment-resistant HIV.⁶³

In many cases, adding lipid-lowering agents may be more beneficial than switching the antiretroviral therapy. For example, a randomized trial in HIV-infected patients with hyperlipidemia found that adding a lipid-lowering agent such as pravastatin or bezafibrate to the unchanged antiretroviral regimen resulted in greater improvement in total cholesterol, LDL-C, and triglyceride levels than switching from a protease inhibitor to either nevirapine or efavirenz.⁶⁴

Given the complexity of prescribing lipid-lowering therapies to patients on antiretroviral therapy, we recommend that providers check with a pharmacist or refer to package inserts and other medical literature if they are unfamiliar with these drug interactions and responses to lipid-lowering therapies.

Managing insulin resistance

Diabetes mellitus is a well-known risk factor for coronary heart disease. The Data Collection on Adverse Events of Anti-HIV Drugs study found a higher incidence of coronary heart disease in HIV-infected patients, with higher rates in those with longer duration of diabetes.⁶⁵ The prevalence of diabetes in HIV-infected populations varies, depending on demographic characteristics,^65,66 prevalence of coinfection with hepatitis C virus,⁶⁶ and prevalence of exposure to antiretroviral drugs⁶⁷ in the study population.

Drugs that lessen insulin resistance include the thiazolidinedione rosiglitazone (Avandia) and the biguanide metformin (Glucophage). In a randomized trial, both drugs, alone or in combination, improved insulin sensitivity in HIV-infected patients, but neither lessened the amount of visceral or subcutaneous fat.⁶⁸

Smoking cessation

Smoking is another well-known modifiable risk factor for coronary heart disease.

The prevalence of smoking is usually higher in HIV patients than in HIV-negative people. For example, a French cohort study reported smoking prevalence rates of 56.6% in HIV-infected men vs 32.7% in HIV-negative men; in women, the rates were 58% vs 28.1%. The 5-year relative risk of coronary heart disease in HIV-infected vs HIV-negative persons was 1.20 for men and 1.59 for women. The estimated attributable risk due to smoking was 65% for men and 29% for women.³

Therefore, smoking cessation should be a top priority in managing cardiovascular risk in HIV-infected patients. In fact, control of modifiable risk factors through lifestyle changes such as smoking cessation, dietary changes, and exercise is likely to have a significant impact on cardiovascular risk in this population.

Widespread use of antiretroviral therapy has caused a remarkable decline in rates of morbidity and death related to acquired immunodeficiency syndrome (AIDS) and has effectively made human immunodeficiency virus (HIV) infection a manageable—although not yet curable— chronic condition. And as the HIV-infected population on antiretroviral therapy ages, the prevalence of chronic conditions (eg, cardiovascular disease, hepatic disease, pulmonary disease, non-AIDS cancers) and deaths attributable to these conditions have also increased.¹

Many of the traditional risk factors for cardiovascular disease in the general population, including smoking, dyslipidemia, and diabetes, are common in HIV-infected patients, and HIV infection itself independently increases the risk of coronary heart disease. In addition, different antiretroviral combinations can contribute, in varying degrees, to changes in lipid levels and insulin resistance, further increasing coronary risk.

Ultimately, however, the immunologic benefits of antiretroviral therapy for individual patients far exceed the modest increase in cardiovascular risk associated with certain regimens. In most cases, careful selection of the initial antiretroviral regimen and the addition of lipid-lowering or glucose-controlling medications (with close attention to drug interactions) can effectively manage the metabolic changes associated with antiretroviral therapy and obviate any premature modification of virologically suppressive regimens.

TRADITIONAL CARDIAC RISK FACTORS IN HIV PATIENTS

The risk of coronary heart disease in HIV patients is influenced mostly by traditional factors such as age, smoking, diabetes, and dyslipidemia, including high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C).²

In various large cohorts, HIV-infected men had a higher prevalence of smoking,³ a lower mean HDL-C level,^3,4 and a higher mean triglyceride level^3,4 than men without HIV infection, placing them at greater risk of coronary heart disease. However, even after adjusting for traditional risk factors, rates of atherosclerosis are still higher in people who are infected with HIV than in those who are not.⁵

EFFECT OF HIV INFECTION ON CORONARY RISK

HIV infection has been shown to increase coronary risk.

In the Kaiser Permanente database,⁶ HIV-positive patients had a significantly higher rate of hospitalizations for coronary heart disease than did people who were not infected.

Similarly, in a cohort study of almost 4,000 HIV-infected patients and more than 1 million controls, the risk of acute myocardial infarction was 75% higher for HIV-positive patients than for HIV-negative patients, even after adjusting for sex, race, hypertension, diabetes, and dyslipidemia.⁵

The Fat Redistribution and Metabolism (FRAM) cross-sectional study⁷ showed that HIV infection was associated with greater carotid intima media thickness, an established marker of atherosclerosis, independently of traditional risk factors and to virtually the same degree as smoking and male sex.

Other studies of subclinical atherosclerosis in HIV patients have yielded disparate results, likely because of differences in study design, methods of measuring carotid thickness, and characteristics of the study populations (eg, prevalence of cardiovascular risk factors and stage of HIV disease). However, a meta-analysis of six prospective cohort studies, three case-control studies, and four cross-sectional studies confirmed that HIV patients had slightly but statistically significantly greater carotid intima media thickness than HIV-negative people.⁸

MECHANISMS BY WHICH HIV MAY PROMOTE CORONARY HEART DISEASE

The pathogenesis of coronary heart disease in HIV infection has not been fully elucidated, but the virus appears to contribute directly to the accelerated development of atherosclerosis. It may do so through direct effects on cholesterol processing and transport, attraction of monocytes to the intimal wall, and activation of monocytes to induce an inflammatory response and endothelial proliferation.

Effects on lipids

In early HIV infection, levels of total cholesterol and HDL-C are lower. In more advanced infection, lower CD4+ lymphocyte counts have been associated with lower levels of apolipoprotein B and with smaller LDL-C particles, suggesting that HIV affects lipid processing and delivery to vessel walls.⁹ HIV infection is also associated with reduced clearance of LDL-C.¹⁰ HIV appears to specifically inhibit the compensatory efflux of excess cholesterol from macrophages, thus promoting the formation of foam cells in atherosclerotic plaque.¹¹

Attraction of monocytes to the vessel wall

In vitro studies also suggest that HIV enhances migration of monocytes into the vascular intima during atherosclerotic plaque development by promoting secretion of the chemokine monocyte chemoattractant protein 1¹² and the expression of endothelial cell adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin.¹³

Inflammation

A recent study suggests that chronic inflammation may be a key contributor to the accelerated development of atherosclerosis in HIV patients. Hsue et al¹⁴ compared carotid intima media thickness and levels of C-reactive protein (a marker of systemic inflammation) in HIV-positive and HIV-negative patients. The carotid intima media thickness was greater in all groups of HIV patients, irrespective of level of viremia or exposure to antiretroviral therapy, than in healthy controls. In addition, C-reactive protein levels remained elevated in HIV-infected participants regardless of their level of viremia.

These findings suggest not only that HIV-associated atherosclerosis is determined by advanced immunodeficiency, high-level viremia, and exposure to antiretroviral drugs, but also that persistent inflammation due to HIV infection may play an important role in accelerated atherosclerosis.

EFFECT OF ANTIRETROVIRAL THERAPY ON CORONARY RISK

Antiretroviral therapy is associated with a small but significant increase in coronary risk.

Medi-Cal,¹⁵ a retrospective study of 28,513 patients, found antiretroviral therapy to be associated with coronary heart disease among patients 18 to 33 years of age (relative risk 2.06, P < .001).

The Data Collection on Adverse Events of Anti-HIV Drugs study¹⁶ prospectively followed 23,437 patients for 94,469 person-years. Adjusted for exposure to nonnucleoside reverse transcriptase inhibitors and for hypertension and diabetes, the relative risk of myocardial infarction per year of protease inhibitor exposure was 1.16 (95% confidence interval [CI] 1.10–1.23). The relative risk was lower after adjusting for serum lipid levels but remained significant at 1.10 (95% CI 1.04–1.18).

Reports have been mixed regarding a possible association between myocardial infarction and the nucleoside reverse transcriptase inhibitor abacavir (Ziagen): several studies found a statistically significant association,^17–20 and others did not.^21–23 Differences in study design (observational cohort studies vs prospective randomized clinical trials), populations studied (differing in age, cardiovascular risk factor prevalence, and whether the patients had already been exposed to treatment), and outcome definition probably contributed to the different conclusions.

On the other hand, several studies have shown that suppression of HIV with antiretroviral therapy actually improves some of the surrogate markers of cardiovascular disease. For example:

• Markers of endothelial function such as flow-mediated vasodilation improve significantly within 4 weeks of a patient’s starting antiretroviral therapy, regardless of the class of antiretroviral drug used.²⁴
• After viral suppression is achieved, levels of the markers of endothelial activation VCAM-1 and P-selectin decline significantly, as do levels of the adipocyte activation marker leptin and the coagulation marker D-dimer.^25,26
• Levels of the anti-inflammatory markers adiponectin and interleukin 10 increase. ^25,26

Interrupting antiretroviral therapy may increase coronary risk

Not only is uncontrolled viral replication in untreated HIV infection associated with cardiovascular disease, but interrupting antiretroviral therapy may result in a supplementary increase in coronary risk.

In the 5,472-patient Strategies for Management of Antiretroviral Therapy (SMART) trial, the rate of cardiovascular disease events was higher if treatment was interrupted than with continuous treatment, with a hazard ratio of 1.57 (95% CI 1.0–2.46, P = .05).²⁷

This association between treatment interruption and coronary events does not appear to be related to the level of viremia.²⁸ Rather, development of cardiovascular disease in HIV-infected patients who interrupt antiretroviral therapy may be mediated, to a large extent, by chronic inflammation in the setting of viral replication. In the treatment-interruption group, levels of the inflammatory cytokine interleukin 6 (IL-6) and the coagulation marker D-dimer were significantly elevated 1 month after randomization, and these differences were strongly associated with death (odds ratio [OR] 12.6, P < .0001 for IL-6; OR 13.1, P < .0001 for D-dimer). Elevated IL-6 levels were also significantly associated with the development of cardiovascular disease (OR 2.8, P = .03).²⁹

METABOLIC COMPLICATIONS OF ANTIRETROVIRAL THERAPY

Persons with HIV infection may experience metabolic complications that are due to HIV itself or to its treatment.

Cross-sectional studies that included HIV-negative patients as controls have demonstrated changes in lipid processing that are known to promote atherosclerosis. For example, persons with HIV infection have smaller LDL-C particles³⁰ and higher levels of circulating oxidized LDL-C.³¹

In the Multicenter AIDS Cohort Study (MACS), after HIV seroconversion, nonfasting total cholesterol, LDL-C, and HDL-C levels declined, which is consistent with a chronic inflammatory state. After antiretroviral therapy was started, lipid levels returned to baseline levels or slightly higher except for HDL-C, which remained low.⁹ These changes may be due to a general “return to health,” or they may be direct medication effects.

Similar patterns were seen in the SMART study.²⁸ Participants randomized to receive intermittent antiretroviral therapy had overall decreases in all lipid levels, with a marked reduction in HDL-C, while those randomized to receive continuous therapy had increased levels of all lipids, including HDL-C, at 12 months. Overall, the ratio of total cholesterol to HDL-C actually increased for participants on episodic therapy, while it decreased in the continuous-treatment group. Along with continued vascular inflammation, the low HDL-C may have contributed to the worse cardiovascular outcomes in patients who received intermittent antiretroviral therapy.

Some lipid changes associated with antiretroviral therapy may actually be beneficial. For example, nonnucleoside reverse transcriptase inhibitors may raise HDL-C levels. However, such increases alone do not necessarily offset the other lipid changes or translate to an observed improvement in coronary risk.³²

The degree of dyslipidemia and specific lipid changes differ among the different classes of antiretroviral drugs and even among the individual drugs within each class. Furthermore, the magnitude of the observed lipid changes varies widely among patients on the same antiretroviral regimen, reflecting the likely important role of host genomics.

While the protease inhibitors and nonnucleoside reverse transcriptase inhibitors have well-described effects on lipids (described in greater detail in the following sections), there have been no reported significant changes in lipid profiles or cardiovascular risk associated with the newest classes, ie, fusion inhibitors such as enfuvirtide (Fuzeon), CC chemokine receptor type 5 (CCR5) receptor inhibitors such as maraviroc (Selzentry), or integrase inhibitors such as raltegravir (Isentress).

Ritonavir (Norvir) and ritonavir-boosted protease inhibitor combinations cause the most significant increases in lipids. Currently, ritonavir is used in low doses to boost the levels of most other protease inhibitors as the standard of care in protease inhibitor-based regimens. However, in most patients, giving ritonavir with protease inhibitors raises lipid levels, particularly triglycerides.

Most boosted protease inhibitor regimens have similar effects on lipid levels, with some exceptions.

Tipranavir (Aptivus) plus ritonavir, for example, markedly raises total cholesterol and triglyceride levels and would not be recommended for patients with dyslipidemia at baseline.³³

Atazanavir (Reyataz)^34,35 plus ritonavir and darunavir (Prezista)³⁶ plus ritonavir cause more modest lipid changes. Unboosted atazanavir raises lipid levels only minimally, if at all,^34,35 but it is no longer a preferred regimen according to US Department of Health and Human Services guidelines.⁴²

Impact of nonnucleoside reverse transcriptase inhibitors on lipids

Efavirenz (Sustiva), a nonnucleoside reverse transcriptase inhibitor, when added to a regimen of two or three nucleoside reverse transcriptase inhibitors, resulted in modest increases in all lipids, including HDL-C (a potentially beneficial change) at 96 weeks compared with a regimen of three nucleoside reverse transcriptase inhibitors only.⁴³

Nevirapine (Viramune), compared with efavirenz, results in a more favorable lipid profile in previously untreated patients, as shown by larger increases in HDL-C and smaller increases in triglycerides at 48 weeks.⁴⁴

Etravirine (Intelence), the newest nonnucleoside reverse transcriptase inhibitor, does not appear to cause any further increase in lipids when added to a regimen containing darunavir-ritonavir and nucleoside agents.⁴⁵

Impact of nucleoside reverse transcriptase inhibitors on lipids

As a class, nucleoside reverse transcriptase inhibitors have been associated with mitochondrial toxicity and insulin resistance,⁴⁶ but the lipid changes associated with them are generally less significant than those caused by protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Nevertheless, within the class, there is considerable variability in lipid changes associated with specific agents.

Stavudine (Zerit), for example, is associated with hypertriglyceridemia.

Tenofovir (Viread), for another example, in combination with emtricitabine (Emtriva) and the nonnucleoside reverse transcriptase inhibitor efavirenz (the three drugs are contained in a formulation called Atripla) was associated with a smaller increase in fasting total cholesterol than with zidovudine-lamivudine and efavirenz at 96 weeks.⁴⁷

A recent placebo-controlled, crossover, pilot study of 17 HIV-infected patients suggested that tenofovir may actually have independent lipid-lowering properties.⁴⁸

Abacavir, as discussed above, has been reported to be associated with a higher risk of myocardial infarction, but this is debatable.

MANAGING CORONARY RISK FACTORS IN HIV-INFECTED PATIENTS

Cardiovascular risk assessment

In HIV patients, cardiovascular risk can be assessed using models derived from large epidemiologic studies such as the Framingham Heart Study.⁴⁹

Current guidelines from the Infectious Diseases Society of America and the AIDS Clinical Trials Group (ACTG) for evaluating and managing dyslipidemia in HIV-infected adults are based on the National Cholesterol Education Program Adult Treatment Panel III.⁵⁰ They recommend obtaining a fasting lipid profile before starting antiretroviral therapy and within 3 to 6 months after starting a new regimen.

The guidelines also recommend stratifying risk by counting the number of cardiovascular risk factors, as is done for the general population. If the patient has more than two factors, the Framingham equation should be used to calculate the 10-year risk of myocardial infarction or cardiac death. Interventions should be offered for modifiable cardiovascular risk factors such as smoking, hypertension, physical inactivity, and diabetes mellitus. LDL-C goals should be determined, and lipid-lowering drugs should be initiated accordingly. If triglyceride levels are 200 to 500 mg/dL and levels of “non-HDL-C” (total cholesterol minus the HDL-C level) are high, a statin is recommended. If the triglyceride level is higher than 500 mg/dL, a fibrate should be started.⁵¹

In HIV patients, statin and fibrate therapy must be considered cautiously, given the important drug interactions with protease inhibitors and especially ritonavir. Many statins are metabolized by cytochrome P3A4, which protease inhibitors inhibit.

Statins generally considered safe to use with most protease inhibitors:

• Pravastatin (Pravachol)
• Rosuvastatin (Crestor)
• Atorvastatin (Lipitor).

Exceptions and caveats:

• Pravastatin should not be prescribed with boosted darunavir.
• Data for fluvastatin (Lescol) in HIV-infected patients on antiretroviral therapy are limited.
• Lovastatin (Mevacor) and simvastatin (Zocor) are contraindicated with protease inhibitor therapy.⁵²
• In contrast to the increase in statin levels seen with protease inhibitors, efavirenz lowers levels of simvastatin, pravastatin, and atorvastatin.^53,54

Ezetimibe (Zetia), which is metabolized independently of the cytochrome P450 system, has been shown to be safe and effective when given to HIV-infected patients on antiretroviral therapy.⁵⁸

Fenofibrate (Lofibra) is recommended by current guidelines for patients with elevated triglyceride levels (> 500 mg/dL).⁵¹ In the ACTG 5087 study, a combination of fenofibrate plus pravastatin was found to be safe and effective in improving lipid profiles.⁵⁹

Long-acting niacin resulted in significant improvements in triglycerides, total cholesterol, HDL-C, and LDL-C after 48 weeks of use, although insulin sensitivity worsened.⁶⁰

Fish oil has been shown to be an effective alternative to fibrates, or it can be used in combination with them.⁶¹

Switching antiretroviral agents vs adding lipid-lowering agents. In some patients with significant dyslipidemia, switching antiretro viral agents may lower lipid levels without compromising virologic control.⁶² However, due to the multifactorial nature of dyslipidemia in HIV patients on antiretroviral therapy, switching the HIV therapy alone may not result in sufficient improvement in the lipid profile⁴⁵ and may be associated with virologic failure, particularly among patients who have underlying treatment-resistant HIV.⁶³

In many cases, adding lipid-lowering agents may be more beneficial than switching the antiretroviral therapy. For example, a randomized trial in HIV-infected patients with hyperlipidemia found that adding a lipid-lowering agent such as pravastatin or bezafibrate to the unchanged antiretroviral regimen resulted in greater improvement in total cholesterol, LDL-C, and triglyceride levels than switching from a protease inhibitor to either nevirapine or efavirenz.⁶⁴

Given the complexity of prescribing lipid-lowering therapies to patients on antiretroviral therapy, we recommend that providers check with a pharmacist or refer to package inserts and other medical literature if they are unfamiliar with these drug interactions and responses to lipid-lowering therapies.

Managing insulin resistance

Diabetes mellitus is a well-known risk factor for coronary heart disease. The Data Collection on Adverse Events of Anti-HIV Drugs study found a higher incidence of coronary heart disease in HIV-infected patients, with higher rates in those with longer duration of diabetes.⁶⁵ The prevalence of diabetes in HIV-infected populations varies, depending on demographic characteristics,^65,66 prevalence of coinfection with hepatitis C virus,⁶⁶ and prevalence of exposure to antiretroviral drugs⁶⁷ in the study population.

Drugs that lessen insulin resistance include the thiazolidinedione rosiglitazone (Avandia) and the biguanide metformin (Glucophage). In a randomized trial, both drugs, alone or in combination, improved insulin sensitivity in HIV-infected patients, but neither lessened the amount of visceral or subcutaneous fat.⁶⁸

Smoking cessation

Smoking is another well-known modifiable risk factor for coronary heart disease.

The prevalence of smoking is usually higher in HIV patients than in HIV-negative people. For example, a French cohort study reported smoking prevalence rates of 56.6% in HIV-infected men vs 32.7% in HIV-negative men; in women, the rates were 58% vs 28.1%. The 5-year relative risk of coronary heart disease in HIV-infected vs HIV-negative persons was 1.20 for men and 1.59 for women. The estimated attributable risk due to smoking was 65% for men and 29% for women.³

Therefore, smoking cessation should be a top priority in managing cardiovascular risk in HIV-infected patients. In fact, control of modifiable risk factors through lifestyle changes such as smoking cessation, dietary changes, and exercise is likely to have a significant impact on cardiovascular risk in this population.

Widespread use of antiretroviral therapy has caused a remarkable decline in rates of morbidity and death related to acquired immunodeficiency syndrome (AIDS) and has effectively made human immunodeficiency virus (HIV) infection a manageable—although not yet curable— chronic condition. And as the HIV-infected population on antiretroviral therapy ages, the prevalence of chronic conditions (eg, cardiovascular disease, hepatic disease, pulmonary disease, non-AIDS cancers) and deaths attributable to these conditions have also increased.¹

Many of the traditional risk factors for cardiovascular disease in the general population, including smoking, dyslipidemia, and diabetes, are common in HIV-infected patients, and HIV infection itself independently increases the risk of coronary heart disease. In addition, different antiretroviral combinations can contribute, in varying degrees, to changes in lipid levels and insulin resistance, further increasing coronary risk.

Ultimately, however, the immunologic benefits of antiretroviral therapy for individual patients far exceed the modest increase in cardiovascular risk associated with certain regimens. In most cases, careful selection of the initial antiretroviral regimen and the addition of lipid-lowering or glucose-controlling medications (with close attention to drug interactions) can effectively manage the metabolic changes associated with antiretroviral therapy and obviate any premature modification of virologically suppressive regimens.

TRADITIONAL CARDIAC RISK FACTORS IN HIV PATIENTS

The risk of coronary heart disease in HIV patients is influenced mostly by traditional factors such as age, smoking, diabetes, and dyslipidemia, including high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C).²

In various large cohorts, HIV-infected men had a higher prevalence of smoking,³ a lower mean HDL-C level,^3,4 and a higher mean triglyceride level^3,4 than men without HIV infection, placing them at greater risk of coronary heart disease. However, even after adjusting for traditional risk factors, rates of atherosclerosis are still higher in people who are infected with HIV than in those who are not.⁵

EFFECT OF HIV INFECTION ON CORONARY RISK

HIV infection has been shown to increase coronary risk.

In the Kaiser Permanente database,⁶ HIV-positive patients had a significantly higher rate of hospitalizations for coronary heart disease than did people who were not infected.

Similarly, in a cohort study of almost 4,000 HIV-infected patients and more than 1 million controls, the risk of acute myocardial infarction was 75% higher for HIV-positive patients than for HIV-negative patients, even after adjusting for sex, race, hypertension, diabetes, and dyslipidemia.⁵

The Fat Redistribution and Metabolism (FRAM) cross-sectional study⁷ showed that HIV infection was associated with greater carotid intima media thickness, an established marker of atherosclerosis, independently of traditional risk factors and to virtually the same degree as smoking and male sex.

Other studies of subclinical atherosclerosis in HIV patients have yielded disparate results, likely because of differences in study design, methods of measuring carotid thickness, and characteristics of the study populations (eg, prevalence of cardiovascular risk factors and stage of HIV disease). However, a meta-analysis of six prospective cohort studies, three case-control studies, and four cross-sectional studies confirmed that HIV patients had slightly but statistically significantly greater carotid intima media thickness than HIV-negative people.⁸

MECHANISMS BY WHICH HIV MAY PROMOTE CORONARY HEART DISEASE

The pathogenesis of coronary heart disease in HIV infection has not been fully elucidated, but the virus appears to contribute directly to the accelerated development of atherosclerosis. It may do so through direct effects on cholesterol processing and transport, attraction of monocytes to the intimal wall, and activation of monocytes to induce an inflammatory response and endothelial proliferation.

Effects on lipids

In early HIV infection, levels of total cholesterol and HDL-C are lower. In more advanced infection, lower CD4+ lymphocyte counts have been associated with lower levels of apolipoprotein B and with smaller LDL-C particles, suggesting that HIV affects lipid processing and delivery to vessel walls.⁹ HIV infection is also associated with reduced clearance of LDL-C.¹⁰ HIV appears to specifically inhibit the compensatory efflux of excess cholesterol from macrophages, thus promoting the formation of foam cells in atherosclerotic plaque.¹¹

Attraction of monocytes to the vessel wall

In vitro studies also suggest that HIV enhances migration of monocytes into the vascular intima during atherosclerotic plaque development by promoting secretion of the chemokine monocyte chemoattractant protein 1¹² and the expression of endothelial cell adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin.¹³

Inflammation

A recent study suggests that chronic inflammation may be a key contributor to the accelerated development of atherosclerosis in HIV patients. Hsue et al¹⁴ compared carotid intima media thickness and levels of C-reactive protein (a marker of systemic inflammation) in HIV-positive and HIV-negative patients. The carotid intima media thickness was greater in all groups of HIV patients, irrespective of level of viremia or exposure to antiretroviral therapy, than in healthy controls. In addition, C-reactive protein levels remained elevated in HIV-infected participants regardless of their level of viremia.

These findings suggest not only that HIV-associated atherosclerosis is determined by advanced immunodeficiency, high-level viremia, and exposure to antiretroviral drugs, but also that persistent inflammation due to HIV infection may play an important role in accelerated atherosclerosis.

EFFECT OF ANTIRETROVIRAL THERAPY ON CORONARY RISK

Antiretroviral therapy is associated with a small but significant increase in coronary risk.

Medi-Cal,¹⁵ a retrospective study of 28,513 patients, found antiretroviral therapy to be associated with coronary heart disease among patients 18 to 33 years of age (relative risk 2.06, P < .001).

The Data Collection on Adverse Events of Anti-HIV Drugs study¹⁶ prospectively followed 23,437 patients for 94,469 person-years. Adjusted for exposure to nonnucleoside reverse transcriptase inhibitors and for hypertension and diabetes, the relative risk of myocardial infarction per year of protease inhibitor exposure was 1.16 (95% confidence interval [CI] 1.10–1.23). The relative risk was lower after adjusting for serum lipid levels but remained significant at 1.10 (95% CI 1.04–1.18).

Reports have been mixed regarding a possible association between myocardial infarction and the nucleoside reverse transcriptase inhibitor abacavir (Ziagen): several studies found a statistically significant association,^17–20 and others did not.^21–23 Differences in study design (observational cohort studies vs prospective randomized clinical trials), populations studied (differing in age, cardiovascular risk factor prevalence, and whether the patients had already been exposed to treatment), and outcome definition probably contributed to the different conclusions.

On the other hand, several studies have shown that suppression of HIV with antiretroviral therapy actually improves some of the surrogate markers of cardiovascular disease. For example:

• Markers of endothelial function such as flow-mediated vasodilation improve significantly within 4 weeks of a patient’s starting antiretroviral therapy, regardless of the class of antiretroviral drug used.²⁴
• After viral suppression is achieved, levels of the markers of endothelial activation VCAM-1 and P-selectin decline significantly, as do levels of the adipocyte activation marker leptin and the coagulation marker D-dimer.^25,26
• Levels of the anti-inflammatory markers adiponectin and interleukin 10 increase. ^25,26

Interrupting antiretroviral therapy may increase coronary risk

Not only is uncontrolled viral replication in untreated HIV infection associated with cardiovascular disease, but interrupting antiretroviral therapy may result in a supplementary increase in coronary risk.

In the 5,472-patient Strategies for Management of Antiretroviral Therapy (SMART) trial, the rate of cardiovascular disease events was higher if treatment was interrupted than with continuous treatment, with a hazard ratio of 1.57 (95% CI 1.0–2.46, P = .05).²⁷

This association between treatment interruption and coronary events does not appear to be related to the level of viremia.²⁸ Rather, development of cardiovascular disease in HIV-infected patients who interrupt antiretroviral therapy may be mediated, to a large extent, by chronic inflammation in the setting of viral replication. In the treatment-interruption group, levels of the inflammatory cytokine interleukin 6 (IL-6) and the coagulation marker D-dimer were significantly elevated 1 month after randomization, and these differences were strongly associated with death (odds ratio [OR] 12.6, P < .0001 for IL-6; OR 13.1, P < .0001 for D-dimer). Elevated IL-6 levels were also significantly associated with the development of cardiovascular disease (OR 2.8, P = .03).²⁹

METABOLIC COMPLICATIONS OF ANTIRETROVIRAL THERAPY

Persons with HIV infection may experience metabolic complications that are due to HIV itself or to its treatment.

Cross-sectional studies that included HIV-negative patients as controls have demonstrated changes in lipid processing that are known to promote atherosclerosis. For example, persons with HIV infection have smaller LDL-C particles³⁰ and higher levels of circulating oxidized LDL-C.³¹

In the Multicenter AIDS Cohort Study (MACS), after HIV seroconversion, nonfasting total cholesterol, LDL-C, and HDL-C levels declined, which is consistent with a chronic inflammatory state. After antiretroviral therapy was started, lipid levels returned to baseline levels or slightly higher except for HDL-C, which remained low.⁹ These changes may be due to a general “return to health,” or they may be direct medication effects.

Similar patterns were seen in the SMART study.²⁸ Participants randomized to receive intermittent antiretroviral therapy had overall decreases in all lipid levels, with a marked reduction in HDL-C, while those randomized to receive continuous therapy had increased levels of all lipids, including HDL-C, at 12 months. Overall, the ratio of total cholesterol to HDL-C actually increased for participants on episodic therapy, while it decreased in the continuous-treatment group. Along with continued vascular inflammation, the low HDL-C may have contributed to the worse cardiovascular outcomes in patients who received intermittent antiretroviral therapy.

Some lipid changes associated with antiretroviral therapy may actually be beneficial. For example, nonnucleoside reverse transcriptase inhibitors may raise HDL-C levels. However, such increases alone do not necessarily offset the other lipid changes or translate to an observed improvement in coronary risk.³²

The degree of dyslipidemia and specific lipid changes differ among the different classes of antiretroviral drugs and even among the individual drugs within each class. Furthermore, the magnitude of the observed lipid changes varies widely among patients on the same antiretroviral regimen, reflecting the likely important role of host genomics.

While the protease inhibitors and nonnucleoside reverse transcriptase inhibitors have well-described effects on lipids (described in greater detail in the following sections), there have been no reported significant changes in lipid profiles or cardiovascular risk associated with the newest classes, ie, fusion inhibitors such as enfuvirtide (Fuzeon), CC chemokine receptor type 5 (CCR5) receptor inhibitors such as maraviroc (Selzentry), or integrase inhibitors such as raltegravir (Isentress).

Ritonavir (Norvir) and ritonavir-boosted protease inhibitor combinations cause the most significant increases in lipids. Currently, ritonavir is used in low doses to boost the levels of most other protease inhibitors as the standard of care in protease inhibitor-based regimens. However, in most patients, giving ritonavir with protease inhibitors raises lipid levels, particularly triglycerides.

Most boosted protease inhibitor regimens have similar effects on lipid levels, with some exceptions.

Tipranavir (Aptivus) plus ritonavir, for example, markedly raises total cholesterol and triglyceride levels and would not be recommended for patients with dyslipidemia at baseline.³³

Atazanavir (Reyataz)^34,35 plus ritonavir and darunavir (Prezista)³⁶ plus ritonavir cause more modest lipid changes. Unboosted atazanavir raises lipid levels only minimally, if at all,^34,35 but it is no longer a preferred regimen according to US Department of Health and Human Services guidelines.⁴²

Impact of nonnucleoside reverse transcriptase inhibitors on lipids

Efavirenz (Sustiva), a nonnucleoside reverse transcriptase inhibitor, when added to a regimen of two or three nucleoside reverse transcriptase inhibitors, resulted in modest increases in all lipids, including HDL-C (a potentially beneficial change) at 96 weeks compared with a regimen of three nucleoside reverse transcriptase inhibitors only.⁴³

Nevirapine (Viramune), compared with efavirenz, results in a more favorable lipid profile in previously untreated patients, as shown by larger increases in HDL-C and smaller increases in triglycerides at 48 weeks.⁴⁴

Etravirine (Intelence), the newest nonnucleoside reverse transcriptase inhibitor, does not appear to cause any further increase in lipids when added to a regimen containing darunavir-ritonavir and nucleoside agents.⁴⁵

Impact of nucleoside reverse transcriptase inhibitors on lipids

As a class, nucleoside reverse transcriptase inhibitors have been associated with mitochondrial toxicity and insulin resistance,⁴⁶ but the lipid changes associated with them are generally less significant than those caused by protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Nevertheless, within the class, there is considerable variability in lipid changes associated with specific agents.

Stavudine (Zerit), for example, is associated with hypertriglyceridemia.

Tenofovir (Viread), for another example, in combination with emtricitabine (Emtriva) and the nonnucleoside reverse transcriptase inhibitor efavirenz (the three drugs are contained in a formulation called Atripla) was associated with a smaller increase in fasting total cholesterol than with zidovudine-lamivudine and efavirenz at 96 weeks.⁴⁷

A recent placebo-controlled, crossover, pilot study of 17 HIV-infected patients suggested that tenofovir may actually have independent lipid-lowering properties.⁴⁸

Abacavir, as discussed above, has been reported to be associated with a higher risk of myocardial infarction, but this is debatable.

MANAGING CORONARY RISK FACTORS IN HIV-INFECTED PATIENTS

Cardiovascular risk assessment

In HIV patients, cardiovascular risk can be assessed using models derived from large epidemiologic studies such as the Framingham Heart Study.⁴⁹

Current guidelines from the Infectious Diseases Society of America and the AIDS Clinical Trials Group (ACTG) for evaluating and managing dyslipidemia in HIV-infected adults are based on the National Cholesterol Education Program Adult Treatment Panel III.⁵⁰ They recommend obtaining a fasting lipid profile before starting antiretroviral therapy and within 3 to 6 months after starting a new regimen.

The guidelines also recommend stratifying risk by counting the number of cardiovascular risk factors, as is done for the general population. If the patient has more than two factors, the Framingham equation should be used to calculate the 10-year risk of myocardial infarction or cardiac death. Interventions should be offered for modifiable cardiovascular risk factors such as smoking, hypertension, physical inactivity, and diabetes mellitus. LDL-C goals should be determined, and lipid-lowering drugs should be initiated accordingly. If triglyceride levels are 200 to 500 mg/dL and levels of “non-HDL-C” (total cholesterol minus the HDL-C level) are high, a statin is recommended. If the triglyceride level is higher than 500 mg/dL, a fibrate should be started.⁵¹

In HIV patients, statin and fibrate therapy must be considered cautiously, given the important drug interactions with protease inhibitors and especially ritonavir. Many statins are metabolized by cytochrome P3A4, which protease inhibitors inhibit.

Statins generally considered safe to use with most protease inhibitors:

• Pravastatin (Pravachol)
• Rosuvastatin (Crestor)
• Atorvastatin (Lipitor).

Exceptions and caveats:

• Pravastatin should not be prescribed with boosted darunavir.
• Data for fluvastatin (Lescol) in HIV-infected patients on antiretroviral therapy are limited.
• Lovastatin (Mevacor) and simvastatin (Zocor) are contraindicated with protease inhibitor therapy.⁵²
• In contrast to the increase in statin levels seen with protease inhibitors, efavirenz lowers levels of simvastatin, pravastatin, and atorvastatin.^53,54

Ezetimibe (Zetia), which is metabolized independently of the cytochrome P450 system, has been shown to be safe and effective when given to HIV-infected patients on antiretroviral therapy.⁵⁸

Fenofibrate (Lofibra) is recommended by current guidelines for patients with elevated triglyceride levels (> 500 mg/dL).⁵¹ In the ACTG 5087 study, a combination of fenofibrate plus pravastatin was found to be safe and effective in improving lipid profiles.⁵⁹

Long-acting niacin resulted in significant improvements in triglycerides, total cholesterol, HDL-C, and LDL-C after 48 weeks of use, although insulin sensitivity worsened.⁶⁰

Fish oil has been shown to be an effective alternative to fibrates, or it can be used in combination with them.⁶¹

Switching antiretroviral agents vs adding lipid-lowering agents. In some patients with significant dyslipidemia, switching antiretro viral agents may lower lipid levels without compromising virologic control.⁶² However, due to the multifactorial nature of dyslipidemia in HIV patients on antiretroviral therapy, switching the HIV therapy alone may not result in sufficient improvement in the lipid profile⁴⁵ and may be associated with virologic failure, particularly among patients who have underlying treatment-resistant HIV.⁶³

In many cases, adding lipid-lowering agents may be more beneficial than switching the antiretroviral therapy. For example, a randomized trial in HIV-infected patients with hyperlipidemia found that adding a lipid-lowering agent such as pravastatin or bezafibrate to the unchanged antiretroviral regimen resulted in greater improvement in total cholesterol, LDL-C, and triglyceride levels than switching from a protease inhibitor to either nevirapine or efavirenz.⁶⁴

Given the complexity of prescribing lipid-lowering therapies to patients on antiretroviral therapy, we recommend that providers check with a pharmacist or refer to package inserts and other medical literature if they are unfamiliar with these drug interactions and responses to lipid-lowering therapies.

Managing insulin resistance

Diabetes mellitus is a well-known risk factor for coronary heart disease. The Data Collection on Adverse Events of Anti-HIV Drugs study found a higher incidence of coronary heart disease in HIV-infected patients, with higher rates in those with longer duration of diabetes.⁶⁵ The prevalence of diabetes in HIV-infected populations varies, depending on demographic characteristics,^65,66 prevalence of coinfection with hepatitis C virus,⁶⁶ and prevalence of exposure to antiretroviral drugs⁶⁷ in the study population.

Drugs that lessen insulin resistance include the thiazolidinedione rosiglitazone (Avandia) and the biguanide metformin (Glucophage). In a randomized trial, both drugs, alone or in combination, improved insulin sensitivity in HIV-infected patients, but neither lessened the amount of visceral or subcutaneous fat.⁶⁸

Smoking cessation

Smoking is another well-known modifiable risk factor for coronary heart disease.

The prevalence of smoking is usually higher in HIV patients than in HIV-negative people. For example, a French cohort study reported smoking prevalence rates of 56.6% in HIV-infected men vs 32.7% in HIV-negative men; in women, the rates were 58% vs 28.1%. The 5-year relative risk of coronary heart disease in HIV-infected vs HIV-negative persons was 1.20 for men and 1.59 for women. The estimated attributable risk due to smoking was 65% for men and 29% for women.³

Therefore, smoking cessation should be a top priority in managing cardiovascular risk in HIV-infected patients. In fact, control of modifiable risk factors through lifestyle changes such as smoking cessation, dietary changes, and exercise is likely to have a significant impact on cardiovascular risk in this population.