Psychosis and schizophrenia

Psychosis is a difficult term to define and is frequently misused, not only in the media but unfortunately among mental health professionals as well. Stigma and fear surround the concept of psychosis, and sometimes the pejorative term "crazy" is used for psychosis. This chapter is not intended to list the diagnostic criteria for all the different mental disorders in which psychosis is either a defining feature or an associated feature. The reader is referred to standard reference sources such as the DSM ( ) of the American Psychiatric Association and theDiagnostic and Statistical Manual ICD ( ) for that information. Although schizophrenia isInternational Classification of Diseases emphasized here, we will approach psychosis as a syndrome associated with a variety of illnesses that are all targets for antipsychotic drug treatment.

Symptom dimensions in schizophrenia

Clinical description of psychosis

Psychosis is a syndrome - that is, a mixture of symptoms - that can be associated with many different psychiatric disorders, but is not a specific disorder itself in diagnostic schemes such as the DSM or ICD. At a minimum, psychosis means delusions and hallucinations. It generally also includes symptoms such as disorganized speech, disorganized behavior, and gross distortions of reality.

Therefore, psychosis can be considered to be a set of symptoms in which a person’s mental capacity, affective response, and capacity to recognize reality, communicate, and relate to others is impaired. Psychotic disorders have psychotic symptoms as their defining features; there are other disorders in which psychotic symptoms may be present, but are not necessary for the diagnosis.

Those as a feature of the diagnosisdisorders that require the presence of psychosis defining include schizophrenia, substance-induced (i.e., drug-induced) psychotic disorders, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, and psychotic disorder due to a general medical condition ( ). Table 4-1 Disorders that may or may not have

as features include mania and depression as well as severalpsychotic symptoms associated cognitive disorders such as Alzheimer’s dementia ( ).Table 4-2

Psychosis itself can be paranoid, disorganized/excited, or depressive. Perceptual distortions and motor disturbances can be associated with any type of psychosis. includePerceptual distortions being distressed by hallucinatory voices; hearing voices that accuse, blame, or threaten punishment; seeing visions;

Table 4-1 Disorders in which psychosis is a defining feature

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reporting hallucinations of touch, taste or odor; or reporting that familiar things and people seem changed. are peculiar, rigid postures; overt signs of tension; inappropriate grinsMotor disturbances or giggles; peculiar repetitive gestures; talking, muttering, or mumbling to oneself; or glancing around as if hearing voices.

In , the patient has paranoid projections, hostile belligerence and grandioseparanoid psychosis expansiveness. includes preoccupation with delusional beliefs; believing thatParanoid projection people are talking about oneself; believing one is being persecuted or being conspired against; and believing people or external forces control one’s actions. is verbal expression ofHostile belligerence feelings of hostility; expressing an attitude of disdain; manifesting a hostile, sullen attitude; manifesting irritability and grouchiness; tending to blame others for problems; expressing feelings of resentment; complaining and finding fault; as well as expressing suspicion of people. Grandiose

is exhibiting an attitude of superiority; hearing voices that praise and extol; believingexpansiveness one has unusual powers or is a well-known personality, or that one has a divine mission.

In a there is conceptual disorganization, disorientation, anddisorganized/excited psychosis excitement. can be characterized by giving answers that are irrelevant orConceptual disorganization incoherent, drifting off the subject, using neologisms, or repeating certain words or phrases.

is not knowing where one is, the season of the year, the calendar year, or one’s ownDisorientation age. is expressing feelings without restraint; manifesting speech that is hurried; exhibitingExcitement an elevated mood; an attitude of superiority;

Table 4-2 Disorders in which psychosis is an associated feature

dramatizing oneself or one’s symptoms; manifesting loud and boisterous speech; exhibiting overactivity or restlessness; and exhibiting excess of speech.

Depressive psychosis is characterized by psychomotor retardation, apathy, and anxious self-punishment and blame. and are manifested by slowed speech;Psychomotor retardation apathy indifference to one’s future; fixed facial expression; slowed movements; deficiencies in recent memory; blocking in speech; apathy toward oneself or one’s problems; slovenly appearance; low or whispered speech; and failure to answer questions. is theAnxious self-punishment and blame tendency to blame or condemn oneself; anxiety about specific matters; apprehensiveness regarding vague future events; an attitude of self-deprecation, manifesting as a depressed mood; expressing feelings of guilt and remorse; preoccupation with suicidal thoughts, unwanted ideas, and specific fears; and feeling unworthy or sinful.

This discussion of clusters of psychotic symptoms does not constitute diagnostic criteria for any psychotic disorder. It is given merely as a description of several types of symptoms in psychosis to give the reader an overview of the nature of behavioral disturbances associated with the various psychotic illnesses.

Schizophrenia is more than a psychosis

Although schizophrenia is the commonest and best-known psychotic illness, it is not synonymous with psychosis, but is just one of many causes of psychosis. Schizophrenia affects 1% of the population, and in the US there are over 300 000 acute schizophrenic episodes annually. Between 25% and 50% of schizophrenia patients attempt suicide, and 10% eventually succeed, contributing to a mortality rate eight times greater than that of the general population. Life expectancy of a patient with schizophrenia may be 20-30 years shorter than the general population, not only due to suicide, but in particular due to premature cardiovascular disease. Accelerated mortality from premature cardiovascular disease in patients with schizophrenia is caused not only by genetic and lifestyle

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factors, such as smoking, unhealthy diet, and lack of exercise leading to obesity and diabetes, but also - sorrily - from treatment with some antipsychotic drugs which themselves cause an increased incidence of obesity and diabetes, and thus increase cardiac risk. In the US, over 20% of all social security benefits are used for the care of patients with schizophrenia. The direct and indirect costs of schizophrenia in the US alone are estimated to be in the tens of billions of dollars every year.

Schizophrenia by definition is a disturbance that must last for six months or longer, including at least one month of delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms. are listed in and shown in Positive symptoms Table 4-3 Figure

. These symptoms4-1

Table 4-3 Positive symptoms of psychosis and schizophrenia

of schizophrenia are often emphasized, since they can be dramatic, can erupt suddenly when a patient decompensates into a psychotic episode (often called a psychotic "break," as in break from reality), and are the symptoms most effectively treated by antipsychotic medications. areDelusions one type of positive symptom, and these usually involve a misinterpretation of perceptions or experiences. The most common content of a delusion in schizophrenia is persecutory, but it may include a variety of other themes including referential (i.e., erroneously thinking that something refers to oneself), somatic, religious, or grandiose. are also a type of positive symptom (Hallucinations

) and may occur in any sensory modality (e.g., auditory, visual, olfactory, gustatory, andTable 4-3 tactile), but auditory hallucinations are by far the most common and characteristic hallucinations in schizophrenia. Positive symptoms generally reflect an of normal functions, and in addition toexcess delusions and hallucinations may also include distortions or exaggerations in language and communication (disorganized speech), as well as in behavioral monitoring (grossly disorganized or catatonic or agitated behavior). Positive symptoms are well known because they are dramatic, are often the cause of bringing a patient to the attention of medical professionals and law enforcement, and are the major target of antipsychotic drug treatments.

Negative symptoms are listed in and and shown in . Classically, there areTables 4-4 4-5 Figure 4-1 at

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Figure 4-1. . The syndrome of schizophrenia consists of aPositive and negative symptoms of schizophrenia mixture of symptoms that are commonly divided into two major categories, positive and negative. Positive symptoms, such as delusions and hallucinations, reflect the development of the symptoms of psychosis; they can be dramatic and may reflect loss of touch with reality. Negative symptoms reflect the loss of normal functions and feelings, such as losing interest in things and not being able to experience pleasure.

least five types of negative symptoms all starting with the letter A ( ):Table 4-5

alogia - dysfunction of communication; restrictions in the fluency and productivity of thought and speech

affective blunting or flattening - restrictions in the range and intensity of emotional expression

asociality - reduced social drive and interaction

anhedonia - reduced ability to experience pleasure

avolition - reduced desire, motivation or persistence; restrictions in the initiation of goal-directed behavior

Table 4-4 Negative symptoms of schizophrenia

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Negative symptoms in schizophrenia, such as blunted affect, emotional withdrawal, poor rapport, passivity and apathetic social withdrawal, difficulty in abstract thinking, stereotyped thinking and lack of spontaneity, commonly are considered a reduction in normal functions and are associated with long periods of hospitalization and poor social functioning. Although this reduction in normal functioning may not be as dramatic as positive symptoms, it is interesting to note that negative symptoms of schizophrenia determine whether a patient ultimately functions well or has a poor outcome. Certainly, patients will have disruptions in their ability to interact with others when their positive symptoms are out of control, but their degree of negative symptoms will largely determine whether patients with schizophrenia can live independently, maintain stable social relationships, or re-enter the workplace.

Although formal rating scales can be used to measure negative symptoms in research studies, in clinical practice it may be more practical to identify and monitor negative symptoms quickly by observation alone ( ) or by some simple questioning ( ). Negative symptoms areFigure 4-2 Figure 4-3 not just part of the syndrome of schizophrenia - they can also be part of a "prodrome" that begins with subsyndromal symptoms that do not meet the diagnostic criteria of schizophrenia and occur before the onset of the full syndrome of schizophrenia. Prodromal negative symptoms are important to detect and monitor over time in high-risk patients so that treatment can be initiated at the first signs of psychosis. Negative

Table 4-5 What are negative symptoms?

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Figure 4-2. . Some negative symptoms of schizophrenia - suchNegative symptoms identified by observation as reduced speech, poor grooming, and limited eye contact - can be identified solely by observing the patient.

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Figure 4-3. . Other negative symptoms of schizophrenia can beNegative symptoms identified by questioning identified by simple questioning. For example, brief questioning can reveal the degree of emotional responsiveness, interest level in hobbies or pursuing life goals, and desire to initiate and maintain social contacts.

symptoms can also persist between psychotic episodes once schizophrenia has begun, and reduce social and occupational functioning in the absence of positive symptoms.

Current antipsychotic drug treatments are limited in their ability to treat negative symptoms, but psychosocial interventions along with antipsychotics can be helpful in reducing negative symptoms. There is even the possibility that instituting treatment for negative symptoms during the prodromal phase of schizophrenia may delay or prevent the onset of the illness, but this is still a matter of current research.

Beyond positive and negative symptoms of schizophrenia

Although not recognized formally as part of the diagnostic criteria for schizophrenia, numerous studies subcategorize the symptoms of this illness into five dimensions: not just positive and negative symptoms, but also cognitive symptoms, aggressive symptoms, and affective symptoms ( ).Figure 4-4 This is perhaps a more sophisticated, if complicated, manner of describing the symptoms of schizophrenia.

Aggressive symptoms such as assaultiveness, verbally abusive behaviors, and frank violence can

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Figure 4-4. . The different symptom domains of schizophrenia areLocalization of symptom domains hypothesized to be regulated by unique brain regions. Positive symptoms of schizophrenia are hypothetically modulated by malfunctioning mesolimbic circuits, while negative symptoms are hypothetically linked to malfunctioning mesocortical circuits and may also involve mesolimbic regions such as the nucleus accumbens, which is part of the brain’s reward circuitry and thus plays a role in motivation. The nucleus accumbens may also be involved in the increased rate of substance use and abuse seen in patients with schizophrenia. Affective symptoms are associated with the ventromedial prefrontal cortex, while aggressive symptoms (related to impulse control) are associated with abnormal information processing in the orbitofrontal cortex and amygdala. Cognitive symptoms are associated with problematic information processing in the dorsolateral prefrontal cortex. Although there is overlap in function among different brain regions, understanding which brain regions may be predominantly involved in specific symptoms can aid in customization of treatment to the particular symptom profile of each individual patient with schizophrenia.

occur with positive symptoms such as delusions and hallucinations, and be confused with positive symptoms. Behavioral interventions may be particularly helpful to prevent violence linked to poor impulsivity by reducing provocations from the environment. Certain antipsychotic drugs such as clozapine, or very high doses of standard antipsychotic drugs, or occasionally the use of two antipsychotic drugs simultaneously, may also be useful for aggressive symptoms and violence in some patients.

It can also be difficult to separate the symptoms of formal cognitive dysfunction from the symptoms of affective dysfunction and from negative symptoms, but research is attempting to localize the specific areas of brain dysfunction for each symptom domain in schizophrenia in the hope of developing better treatments for the often-neglected negative, cognitive, and affective symptoms of schizophrenia. In particular, neuropsychological assessment batteries are being developed to quantify cognitive symptoms, in order to detect cognitive improvement after treatment with a number of novel psychotropic drugs currently being tested. Cognitive symptoms of schizophrenia are impaired attention and impaired information processing manifested as impaired verbal fluency (ability to produce spontaneous speech), problems with serial learning (of a list of items or a sequence of events), and impairment in vigilance for executive functioning (problems with sustaining and focusing attention, concentrating, prioritizing, and modulating behavior based upon social cues).

Important cognitive symptoms of schizophrenia are listed in . These do not includeTable 4-6 symptoms of dementia and memory disturbance more characteristic of Alzheimer’s disease, but cognitive symptoms of schizophrenia emphasize "executive dysfunction," which includes problems representing and maintaining goals, allocating attentional resources, evaluating and monitoring performance, and utilizing these skills to solve problems. Cognitive symptoms of schizophrenia are important to recognize and monitor because they are the single strongest correlate of real-world functioning, even stronger than negative symptoms.

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Table 4-6 Cognitive symptoms of schizophrenia

Symptoms of schizophrenia are not necessarily unique to schizophrenia

It is important to recognize that several illnesses other than schizophrenia can share some of the same five symptom dimensions as described here for schizophrenia and shown in . Thus,Figure 4-4 disorders in addition to schizophrenia that can have include bipolar disorder,positive symptoms schizoaffective disorder, psychotic depression, Alzheimer’s disease and other organic dementias, childhood psychotic illnesses, drug-induced psychoses, and others. can alsoNegative symptoms occur in other disorders and can also overlap with cognitive and affective symptoms that occur in these other disorders. However, as a primary deficit state, negative symptoms are fairly unique to schizophrenia. Schizophrenia is certainly not the only disorder with . Autism,cognitive symptoms post-stroke (vascular or multi-infarct) dementia, Alzheimer’s disease, and many other organic dementias (Parkinsonian/Lewy body dementia, frontotemporal/Pick’s dementia, etc.) can also be associated with cognitive dysfunctions similar to those seen in schizophrenia.

Affective symptoms are frequently associated with schizophrenia but this does not necessarily mean that they fulfill the diagnostic criteria for a comorbid anxiety or affective disorder. Nevertheless, depressed mood, anxious mood, guilt, tension, irritability, and worry frequently accompany schizophrenia. These various symptoms are also prominent features of major depressive disorder, psychotic depression, bipolar disorder, schizoaffective disorder, organic dementias, childhood psychotic disorders, and treatment-resistant cases of depression, bipolar disorder, and schizophrenia, among others. Finally, occur in numerous otheraggressive and hostile symptoms disorders, especially those with problems of impulse control. Symptoms include overt hostility, such as verbal or physical abusiveness or assault, self-injurious behaviors including suicide, and arson or other property damage. Other types of impulsiveness such as sexual acting out are also in this category of aggressive and hostile symptoms. These same symptoms are frequently associated with bipolar disorder, childhood psychosis, borderline personality disorder, antisocial personality disorder, drug abuse, Alzheimer’s and other dementias, attention deficit hyperactivity disorder, conduct disorders in children, and many others.

Brain circuits and symptom dimensions in schizophrenia

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The various symptoms of schizophrenia are hypothesized to be localized in unique brain regions ( ). Specifically, the positive symptoms of schizophrenia have long been hypothesized to beFigure 4-4

localized to malfunctioning mesolimbic circuits, especially involving the nucleus accumbens. The nucleus accumbens is considered to be part of the brain’s reward circuitry, so it is not surprising that problems with reward and motivation in schizophrenia, symptoms that can overlap with negative symptoms and lead to smoking, drug and alcohol abuse, may be linked to this brain area as well. The prefrontal cortex is considered to be a key node in the nexus of malfunctioning cerebral circuitry responsible for each of the remaining symptoms of schizophrenia: specifically, the mesocortical and ventromedial prefrontal cortex with negative symptoms and affective symptoms, the dorsolateral prefrontal cortex with cognitive symptoms, and the orbitofrontal cortex and its connections to amygdala with aggressive, impulsive symptoms ( ).Figure 4-4

This model is obviously oversimplified and reductionistic, because every brain area has several functions, and every function is certainly distributed to more than one brain area. Nevertheless, allocating specific symptom dimensions to unique brain areas not only assists research studies, but has both heuristic and clinical value. Specifically, every patient has unique symptoms, and unique responses to medication. In order to optimize and individualize treatment, it can be useful to consider which specific symptoms any given patient is expressing, and therefore which areas of that particular patient’s brain are hypothetically malfunctioning ( ). Each brain area has uniqueFigure 4-4 neurotransmitters, receptors, enzymes, and genes that regulate it, with some overlap, but also with some unique regional differences, and knowing this can assist the clinician in choosing medications and in monitoring the effectiveness of treatment.

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Antipsychotic agents

This chapter will explore antipsychotic drugs, with an emphasis on treatments for schizophrenia. These treatments include not only conventional antipsychotic drugs, but also the newer atypical antipsychotic drugs that have largely replaced the older conventional agents. Atypical antipsychotics are really misnamed, since they are also used as treatments for both the manic and depressed phases of bipolar disorder, as augmenting agents for treatment-resistant depression, and "off-label" for various other disorders, such as treatment-resistant anxiety disorders. The reader is referred to standard reference manuals and textbooks for practical prescribing information, such as drug doses, because this chapter on antipsychotic drugs will

Figure 5-1. . ThroughoutQualitative and semi-quantitative representation of receptor binding properties this chapter, the receptor binding properties of the atypical antipsychotics are represented both graphically and semi-quantitatively. Each drug is represented as a blue sphere, with its most potent binding properties depicted along the outer edge of the sphere. Additionally, each drug has a series of colored boxes associated with it. Each colored box represents a different binding property, and binding strength is indicated by the size of the box and the number of plus signs. Within the colored box series for any particular antipsychotic, larger boxes with more plus signs (positioned to the left) indicate stronger binding affinity, while smaller boxes with fewer plus signs (positioned to the right) represent weaker binding affinity. The series of boxes associated with each drug are arranged such that the size and positioning of a box reflect the binding potency for a particular receptor. The vertical dotted line cuts through the dopamine 2 (D ) receptor binding box, with binding properties that are more2 potent than D on the left and those that are less potent than D on the right. All binding properties are based on2 2 the mean values of published K (binding affinity) data ( ). The semi-quantitative depictioni http://pdsp.med.unc.edu

used throughout this chapter provides a quick visual reference of how strongly a particular drug binds to a particular receptor. It also allows for easy comparison of a drug's binding properties with those of other atypical antipsychotics.

emphasize basic pharmacologic concepts of mechanism of action and not practical issues such as how to prescribe these drugs (for that information see for example Stahl's Essential

, which is a companion to this textbook).Psychopharmacology: the Prescriber's Guide

Antipsychotic drugs exhibit possibly the most complex pharmacologic mechanisms of any drug class within the field of clinical psychopharmacology. The pharmacologic concepts developed here should help the reader understand the rationale for how to use each of the different antipsychotic agents,

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based upon their interactions with different neurotransmitter systems ( ). Such interactionsFigure 5-1 can often explain both the therapeutic actions and the side effects of various antipsychotic medications and thus can be very helpful background information for prescribers of these therapeutic agents.

Conventional antipsychotics

What makes an antipsychotic "conventional"?

In this section we will discuss the pharmacologic properties of the first drugs that were proven to effectively treat schizophrenia. A list of many conventional antipsychotic drugs is given in .Table 5-1 These drugs are usually called antipsychotics, but they are sometimes also called conventional

antipsychotics, or antipsychotics, or antipsychotics. The earliestclassical typical first-generation effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations more than

Table 5-1 Some conventional antipsychotics still in use

60 years ago, rather than from scientific knowledge of the neurobiological basis of psychosis, or of the mechanism of action of effective antipsychotic agents. Thus, the first antipsychotic drugs were discovered by accident in the 1950s when a drug with antihistamine properties (chlorpromazine) was serendipitously observed to have antipsychotic effects when this putative antihistamine was tested in schizophrenia patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions

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in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic action.

Early in the testing process, chlorpromazine and other antipsychotic agents were all found to cause "neurolepsis," known as an extreme form of slowness or absence of motor movements as well as behavioral indifference in experimental animals. The original antipsychotics were first discovered largely by their ability to produce this effect in experimental animals, and are thus sometimes called "neuroleptics." A human counterpart of neurolepsis is also caused by these original (i.e., conventional) antipsychotic drugs and is characterized by psychomotor slowing, emotional quieting, and affective indifference.

Figure 5-2. . Conventional antipsychotics, also called first-generation antipsychotics or typicalD antagonist2 antipsychotics, share the primary pharmacological property of D antagonism, which is responsible not only for2 their antipsychotic efficacy but also for many of their side effects. Shown here is an icon representing this single pharmacological action.

D receptor antagonism makes an antipsychotic conventional2

By the 1970s it was widely recognized that the key pharmacologic property of all "neuroleptics" with antipsychotic properties was their ability to block dopamine D receptors ( ). This action has2 Figure 5-2

proven to be responsible not only for the antipsychotic efficacy of conventional antipsychotic drugs, but also for most of their undesirable side effects, including "neurolepsis."

The therapeutic actions of conventional antipsychotic drugs are hypothetically due to blockade of D2 receptors specifically in the mesolimbic dopamine pathway ( ). This has the effect ofFigure 5-3

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reducing the hyperactivity in this pathway that is postulated to cause the positive symptoms of psychosis, as discussed in ( and ). All conventional antipsychotics reduceChapter 4 Figures 4-12 4-13 positive psychotic symptoms about equally well in schizophrenia patients studied in large multicenter trials if they are dosed to block a substantial number of D receptors there ( ).2 Figure 5-4

Unfortunately, in order to block adequate numbers of D receptors in the mesolimbic dopamine2 pathway to

Figure 5-3. . In untreated schizophrenia, the mesolimbicMesolimbic dopamine pathway and D antagonists2 dopamine pathway is hypothesized to be hyperactive, indicated here by the pathway appearing red as well as by the excess dopamine in the synapse. This leads to positive symptoms such as delusions and hallucinations. Administration of a D antagonist, such as a conventional antipsychotic, blocks dopamine from binding to the D2 2 receptor, which reduces hyperactivity in this pathway and thereby reduces positive symptoms as well.

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Figure 5-4. . All known antipsychoticsHypothetical thresholds for conventional antipsychotic drug effects bind to the dopamine 2 receptor, with the degree of binding determining whether one experiences therapeutic and/or side effects. For most conventional antipsychotics, the degree of D2 receptor binding in the mesolimbic pathway needed for antipsychotic effects is close to 80%, while D2 receptor occupancy greater than 80% in the dorsal striatum is associated with extrapyramidal side effects (EPS) and in the pituitary is associated with hyperprolactinemia. For conventional antipsychotics (i.e,. pure D2 antagonists) it is assumed that the same number of D2 receptors is blocked in all brain areas. Thus, there is a narrow window between the threshold for antipsychotic efficacy and that for side effects in terms of D2 binding.

quell positive symptoms, one must simultaneously block the same number of D receptors2 throughout the brain, and this causes undesirable side effects as a "high cost of doing business" with conventional antipsychotics ( through ). Although modern neuroimaging techniquesFigures 5-5 5-8 are able to measure directly the blockade of D receptors in the dorsal (motor) striatum of the2 nigrostriatal pathway, as shown in , for conventional antipsychotics it is assumed that theFigure 5-4 same number of D receptors is blocked in all brain areas, including the ventral limbic area of2 striatum known as the nucleus accumbens of the mesolimbic dopamine pathway, the prefrontal cortex of the mesocortical dopamine pathway, and the pituitary gland of the tuberoinfundibular dopamine pathway.

Neurolepsis

D receptors in the mesolimbic dopamine system are postulated to mediate not only the positive2 symptoms of psychosis, but also the normal reward system of the brain, and the nucleus accumbens is widely considered to be the "pleasure center" of the brain. It may be the final common pathway of all reward and reinforcement, including not only normal reward (such as the pleasure of eating good food, orgasm, listening to music) but also the artificial reward of substance abuse. If D receptors are2 stimulated in some parts of the mesolimbic pathway, this can lead to the experience of pleasure. Thus, if D receptors in the mesolimbic system are blocked, this may not only reduce positive2 symptoms of schizophrenia, but also block reward mechanisms, leaving patients apathetic, anhedonic, lacking motivation, interest, and joy from social interactions, a state very similar to that of negative symptoms of schizophrenia. The near shutdown of the mesolimbic dopamine pathway necessary to improve the positive symptoms of psychosis ( ) may contribute to worseningFigure 5-4 of anhedonia, apathy, and negative symptoms, and this may be a partial explanation for the high incidence of smoking and drug abuse in schizophrenia.

Antipsychotics also block D receptors in the mesocortical DA pathway ( ), where DA may2 Figure 5-5

already be deficient in schizophrenia (see through ). This can cause or worsenFigures 4-14 4-16

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negative and cognitive symptoms even though there is only a low density of D receptors in the2 cortex. An adverse behavioral state can be produced by conventional antipsychotics, and is sometimes called the "neuroleptic-induced deficit syndrome" because it looks so much like the negative symptoms produced by schizophrenia itself, and is reminiscent of "neurolepsis" in animals.

Extrapyramidal symptoms and tardive dyskinesia

When a substantial number of D receptors are blocked in the nigrostriatal DA pathway, this will2 produce various disorders of movement that can appear very much like those in Parkinson's disease; this is why these movements are sometimes called drug-induced

Figure 5-5. . In untreated schizophrenia, theMesocortical dopamine pathway and D antagonists2 mesocortical dopamine pathways to dorsolateral prefrontal cortex (DLPFC) and to ventromedial prefrontal cortex (VMPFC) are hypothesized to be hypoactive, indicated here by the dotted outlines of the pathway. This hypoactivity is related to cognitive symptoms (in the DLPFC), negative symptoms (in the DLPFC and VMPFC), and affective symptoms of schizophrenia (in the VMPFC). Administration of a D antagonist could further reduce2 activity in this pathway and thus not only not improve such symptoms but actually potentially worsen them.

parkinsonism. Since the nigrostriatal pathway is part of the extrapyramidal nervous system, these motor side effects associated with blocking D receptors in this part of the brain are sometimes also2 called extrapyramidal symptoms, or EPS ( and ).Figures 5-4 5-6

Worse yet, if these D receptors in the nigrostriatal DA pathway are blocked chronically ( ),2 Figure 5-7

they can produce a hyperkinetic movement disorder known as tardive dyskinesia. This movement disorder causes facial and tongue movements, such as constant chewing, tongue protrusions, facial grimacing, and also limb movements that can be quick, jerky, or choreiform (dancing). Tardive dyskinesia is thus caused by long-term administration of conventional antipsychotics and is thought to be mediated by changes, sometimes irreversible, in the D receptors of the nigrostriatal DA2 pathway. Specifically, these receptors are hypothesized to become supersensitive or to "upregulate" (i.e., increase in number), perhaps in a futile attempt to overcome drug-induced blockade of D2 receptors in the striatum ( ).Figure 5-7

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About 5% of patients maintained on conventional antipsychotics will develop tardive dyskinesia every year (i.e., about 25% of patients by 5 years), not a very encouraging prospect for a lifelong illness starting in the early twenties. The risk of developing tardive

Figure 5-6. . The nigrostriatal dopamine pathway isNigrostriatal dopamine pathway and D antagonists2 theoretically unaffected in untreated schizophrenia. However, blockade of D receptors, as with a conventional2 antipsychotic, prevents dopamine from binding there and can cause motor side effects that are often collectively termed extrapyramidal symptoms (EPS).

dyskinesia in elderly subjects may be as high as 25% within the first year of exposure to conventional antipsychotics. However, if D receptor blockade is removed early enough, tardive dyskinesia may2 reverse. This reversal is theoretically due to a "resetting" of these D receptors by an appropriate2 decrease in the number or sensitivity of them in the nigrostriatal pathway once the antipsychotic drug that had been blocking these receptors is removed. However, after long-term treatment, the D2 receptors apparently cannot or do not reset back to normal, even when conventional antipsychotic drugs are discontinued. This leads to tardive dyskinesia that is irreversible, continuing whether conventional antipsychotic drugs are administered or not.

Is there any way to predict those who will be harmed with the development of tardive dyskinesia after chronic treatment with conventional antipsychotics? Patients who develop EPS early in treatment may be twice as likely to develop tardive dyskinesia if treatment with a conventional antipsychotic is continued chronically. Also, specific genotypes of dopamine receptors may confer important genetic risk factors for developing tardive dyskinesia with chronic treatment using a conventional antipsychotic. Risk of new cases of tardive

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Figure 5-7. . Long-term blockade of D receptors in the nigrostriatal dopamine pathway canTardive dyskinesia 2 cause upregulation of those receptors, which may lead to a hyperkinetic motor condition known as tardive dyskinesia, characterized by facial and tongue movements (e.g., tongue protrusions, facial grimaces, chewing) as well as quick, jerky limb movements. This upregulation may be the consequence of the neuron's futile attempt to overcome drug-induced blockade of its dopamine receptors.

dyskinesia, however, can diminish considerably after 15 years of treatment, presumably because patients who have not developed tardive dyskinesia despite 15 years of treatment with a conventional antipsychotic have lower genetic risk factors for it.

A rare but potentially fatal complication called the "neuroleptic malignant syndrome," associated with extreme muscular rigidity, high fevers, coma, and even death, and possibly related in part to D2 receptor blockade in the nigrostriatal pathway, can also occur with conventional antipsychotic agents.

Prolactin elevation

Dopamine D receptors in the tuberoinfundibular DA pathway are also blocked by conventional2 antipsychotics, and this causes plasma prolactin concentrations to rise, a condition called hyperprolactinemia ( ). This is associated with conditions called galactorrhea (i.e., breastFigure 5-8 secretions) and amenorrhea (i.e., irregular or lack of menstrual periods). Hyperprolactinemia may thus interfere with fertility, especially in women. Hyperprolactinemia might lead to more rapid demineralization of bones, especially in postmenopausal women who are not taking estrogen replacement therapy. Other possible problems associated with elevated prolactin levels may include sexual dysfunction and weight gain, although the role of prolactin in causing such problems is not clear.

The dilemma of blocking D dopamine receptors in all dopamine pathways2

It should now be obvious that the use of conventional antipsychotic drugs presents a powerful dilemma. That is, there is no doubt that conventional antipsychotic medications exert dramatic therapeutic actions upon positive symptoms of schizophrenia by blocking hyperactive dopamine neurons in the mesolimbic dopamine pathway. However, there are dopamine pathways in theseveral brain, and it appears that blocking dopamine receptors in of them is useful ( ),only one Figure 5-3 whereas blocking dopamine receptors in the remaining pathways may be harmful (Figures 5-4 through ). The pharmacologic5-8

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Figure 5-8. . The tuberoinfundibular dopamineTuberoinfundibular dopamine pathway and D antagonists2 pathway, which projects from the hypothalamus to the pituitary gland, is theoretically "normal" in untreated schizophrenia. D antagonists reduce activity in this pathway by preventing dopamine from binding to D2 2 receptors. This causes prolactin levels to rise, which is associated with side effects such as galactorrhea (breast secretions) and amenorrhea (irregular menstrual periods).

quandary here is what to do if one wishes simultaneously to dopamine in the mesolimbicdecrease dopamine pathway in order to treat positive psychotic symptoms theoretically mediated by hyperactive mesolimbic dopamine neurons and yet dopamine in the mesocortical dopamineincrease pathway to treat negative and cognitive symptoms, while leaving dopaminergic tone unchanged in both the nigrostriatal and tuberoinfundibular dopamine pathways to avoid side effects. This dilemma may have been addressed in part by the atypical antipsychotic drugs described in the following sections, and is one of the reasons why the atypical antipsychotics have largely replaced conventional antipsychotic agents in the treatment of schizophrenia and other psychotic disorders throughout the world.

Muscarinic cholinergic blocking properties of conventional antipsychotics

In addition to blocking D receptors in all dopamine pathways ( through ), conventional2 Figures 5-3 5-8

antipsychotics have other important pharmacologic

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Figure 5-9. . Shown here is an icon representing a conventional antipsychoticConventional antipsychotic drug. Conventional antipsychotics have pharmacological properties in addition to dopamine D antagonism. The2 receptor profiles differ for each agent, contributing to divergent side-effect profiles. However, some important characteristics that multiple agents share are the ability to block muscarinic cholinergic receptors, histamine H1 receptors, and/or -adrenergic receptors.1

properties ( ). One particularly important pharmacologic action of some conventionalFigure 5-9 antipsychotics is their ability to block muscarinic M -cholinergic receptors ( through ).1 Figures 5-9 5-11

This can cause undesirable side effects such as dry mouth, blurred vision, constipation, and cognitive blunting ( ). Differing degrees of muscarinic cholinergic blockade may alsoFigure 5-10 explain why some conventional antipsychotics have a lesser propensity to produce extrapyramidal side effects (EPS) than others. That is, those conventional antipsychotics that cause more EPS are the agents that have only anticholinergic properties, whereas those conventional antipsychoticsweak that cause fewer EPS are the agents that have anticholinergic properties.stronger

How does muscarinic cholinergic receptor blockade reduce the EPS caused by dopamine D2 receptor blockade in the nigrostriatal pathway? The reason seems to be based on the fact that dopamine and acetylcholine have a reciprocal relationship with each other in the nigrostriatal pathway ( ).Figure 5-11

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Figure 5-10. . In this diagram, the icon of aSide effects of muscarinic cholinergic receptor blockade conventional antipsychotic drug is shown with its M anticholinergic/antimuscarinic portion inserted into1 acetylcholine receptors, causing the side effects of constipation, blurred vision, dry mouth, and drowsiness.

Figure 5-11

A. . Dopamine and acetylcholine have a reciprocalReciprocal relationship of dopamine and acetylcholine relationship in the nigrostriatal dopamine pathway. Dopamine neurons here make postsynaptic connections with the dendrite of a cholinergic neuron. Normally, dopamine suppresses acetylcholine activity (no acetylcholine being released from the cholinergic axon on the right).

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B. . This figure shows what happens to acetylcholine activityDopamine, acetylcholine, and D antagonism2 when dopamine receptors are blocked. As dopamine normally suppresses acetylcholine activity, removal of dopamine inhibition causes an increase in acetylcholine activity. Thus if dopamine receptors are blocked at the D receptors on the cholinergic dendrite on the left, then acetylcholine becomes overly active, with enhanced2 release of acetylcholine from the cholinergic axon on the right. This is associated with the production of extrapyramidal symptoms (EPS). The pharmacological mechanism of EPS therefore seems to be a relative dopamine deficiency and a relative acetylcholine excess.

C. . One compensation for the overactivity that occurs whenD antagonism and anticholinergic agents2 dopamine receptors are blocked is to block the acetylcholine receptors with an anticholinergic agent (M1 receptors being blocked by an anticholinergic on the far right). Thus, anticholinergics overcome excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked by conventional antipsychotics. This also means that extrapyramidal symptoms (EPS) are reduced.

Dopamine neurons in the nigrostriatal dopamine pathway make postsynaptic connections with cholinergic neurons ( ). Dopamine normally acetylcholine release fromFigure 5-11A inhibits postsynaptic nigrostriatal cholinergic neurons, thus suppressing acetylcholine activity there (Figure

). If dopamine can no longer suppress acetylcholine release because dopamine receptors are5-11A

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being blocked by a conventional antipsychotic drug, then acetylcholine becomes overly active ( ).Figure 5-11B

One compensation for this overactivity of acetylcholine is to block it with an anticholinergic agent ( ). Thus, drugs with anticholinergic actions will diminish the excess acetylcholine activityFigure 5-11C

caused by removal of dopamine inhibition when dopamine receptors are blocked ( and Figures 5-10 ). If anticholinergic properties are present in the same drug with D blocking properties, they5-11C 2

will tend to mitigate the effects of D blockade in the nigrostriatal dopamine pathway. Thus,2 conventional antipsychotics with potent anticholinergic properties have lower EPS than conventional antipsychotics with weak anticholinergic properties. Furthermore, the effects of D blockade in the2 nigrostriatal system can be mitigated by co-administering an agent with anticholinergic properties. This has led to the common strategy of giving anticholinergic agents along with conventional antipsychotics in order to reduce EPS. Unfortunately, this concomitant use of anticholinergic agents does not lessen the ability of the conventional antipsychotics to cause tardive dyskinesia. It also causes the well-known side effects associated with anticholinergic agents, such as dry mouth, blurred vision, constipation, urinary retention, and cognitive dysfunction ( ).Figure 5-10

Other pharmacologic properties of conventional antipsychotic drugs

Still other pharmacologic actions are associated with the conventional antipsychotic drugs. These include generally undesired blockade of histamine H receptors ( ) causing weight gain and1 Figure 5-9

drowsiness, as well as blockade of -adrenergic receptors causing cardiovascular side effects such1 as orthostatic hypotension and drowsiness. Conventional antipsychotic agents differ in terms of their ability to block these various receptors represented in . For example, the popularFigure 5-9 conventional antipsychotic haloperidol has relatively little anticholinergic or antihistaminic binding activity, whereas the classic conventional antipsychotic chlorpromazine has potent anticholinergic and antihistaminic binding. Because of this, conventional antipsychotics differ somewhat in their side-effect profiles, even if they do not differ overall in their therapeutic profiles. That is, some conventional antipsychotics are more sedating than others, some have more ability to cause cardiovascular side effects than others, some have more ability to cause EPS than others.

A somewhat old-fashioned way to subclassify conventional antipsychotics is "low potency" versus "high potency" ( ). In general, as the name implies, low-potency agents require higher dosesTable 5-1 than high-potency agents, but, in addition, low-potency agents tend to have more of the additional properties discussed here than do the so-called high-potency agents: namely, low-potency agents have greater anticholinergic, antihistaminic, and antagonist properties than high-potency agents,1 and thus are probably more sedating in general. A number of conventional antipsychotics are available in long-acting depot formulations ( ).Table 5-1

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Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years A Randomized Clinical Trial Jeff D. Williamson, MD, MHS; Mark A. Supiano, MD; William B. Applegate, MD, MPH; Dan R. Berlowitz, MD; Ruth C. Campbell, MD, MSPH; Glenn M. Chertow, MD; Larry J. Fine, MD; William E. Haley, MD; Amret T. Hawfield, MD; Joachim H. Ix, MD, MAS; Dalane W. Kitzman, MD; John B. Kostis, MD; Marie A. Krousel-Wood, MD; Lenore J. Launer, PhD; Suzanne Oparil, MD; Carlos J. Rodriguez, MD, MPH; Christianne L. Roumie, MD, MPH; Ronald I. Shorr, MD, MS; Kaycee M. Sink, MD, MAS; Virginia G. Wadley, PhD; Paul K. Whelton, MD; Jeffrey Whittle, MD; Nancy F. Woolard; Jackson T. Wright Jr, MD, PhD; Nicholas M. Pajewski, PhD; for the SPRINT Research Group

IMPORTANCE The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain.

OBJECTIVE To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP targets in persons aged 75 years or older with hypertension but without diabetes.

DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015.

INTERVENTIONS Participants were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1319).

MAIN OUTCOMES AND MEASURES The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome.

RESULTS Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]).

CONCLUSIONS AND RELEVANCE Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01206062

JAMA. 2016;315(24):2673-2682. doi:10.1001/jama.2016.7050 Published online May 19, 2016.

Editorial page 2669

Author Video Interview at jama.com

Supplemental content at jama.com

CME Quiz at jamanetworkcme.com and CME Questions page 2728

Author Affiliations: Author affiliations are listed at the end of this article.

Group Information: The members of the SPRINT Research Group have been published elsewhere.

Corresponding Author: Jeff D. Williamson, MD, MHS, Section on Gerontology and Geriatric Medicine, Sticht Center on Aging, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 ([email protected]).

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I n the United States, 75% of persons older than 75 years havehypertension, for whom cardiovascular disease complica-tions are a leading cause of disability, morbidity, and mortality.1-3 Current guidelines provide inconsistent recom- mendations regarding the optimal systolic blood pressure (SBP) treatment target in geriatric populations.4 European guide- line committees have recommended treatment initiation only above 160 mm Hg for persons aged 80 years or older.5 A re- cent US guideline, a report from the panel appointed to the Eighth Joint National Committee, recommended a SBP treat- ment target of 150 mm Hg for adults aged 60 years or older.6

However, a report from a minority of the members argued to retain the previously recommended SBP treatment goal of 140 mm Hg, highlighting the lack of consensus.7

Whether treatment targets should consider factors such as frailty or functional status is also unknown. Observational studies have noted differential associations among elevated blood pressure (BP) and cardiovascular disease, stroke, and mortality risk when analyses are stratified according to mea- sures of functional status.8-10 A recent secondary analysis of the Systolic Hypertension in the Elderly Program showed that the benefit of antihypertensive therapy was limited to partici- pants without a self-reported physical ability limitation.11 In contrast, analyses from the Hypertension in the Very Elderly Trial (HYVET) showed a consistent benefit with antihyperten- sive therapy on outcomes irrespective of frailty status.12

The Systolic Blood Pressure Intervention Trial (SPRINT) recently reported that participants assigned to an intensive SBP treatment target of less than 120 mm Hg vs the standard SBP treatment goal of less than 140 mm Hg had a 25% lower rela- tive risk of major cardiovascular events and death, and a 27% lower relative risk of death from any cause.13 This trial was spe- cifically funded to enhance recruitment of a prespecified sub- group of adults aged 75 years or older, and the study protocol (appears in Supplement 1) also included measures of functional status and frailty. This article details results for the prespecified subgroup of adults aged 75 years or older with hypertension.

Methods Population The design, eligibility, and baseline characteristics of SPRINT have been described.14 The trial protocol was approved by the institutional review board at each participating site. Study participants signed written informed consent and were required to be at increased risk for cardiovascular disease (based on a history of clinical or subclinical cardiovascular disease, chronic kidney disease [CKD], a 10-year Framingham General cardiovascular disease risk ≥15%, or age ≥75 years). A person was excluded if he or she had type 2 diabetes, a his- tory of stroke, symptomatic heart failure within the past 6 months or reduced left ventricular ejection fraction (<35%), a clinical diagnosis of or treatment for dementia, an expected survival of less than 3 years, unintentional weight loss (>10% of body weight) during the preceding 6 months, an SBP of less than 110 mm Hg following 1 minute of standing, or resided in a nursing home.

Study Measurements Sociodemographic data were collected at baseline, whereas both clinical and laboratory data were obtained at baseline and every 3 months. Race and ethnicity information was ob- tained via self-report. Blood pressure was determined using the mean of 3 properly sized automated cuff readings, taken 1 minute apart after 5 minutes of quiet rest without staff in the room. Gait speed was measured via a timed 4-m walk per- formed twice at the participant’s usual pace from a standing start. The use of an assistive device was permitted if typically used by the participant to walk short distances. The faster of the 2 gait speeds (measured in meters/second) was used in the analysis. Frailty status at randomization was quantified using a previously reported 37-item frailty index.15

Clinical Outcomes A committee unaware of treatment assignment adjudicated the protocol-specified clinical outcomes. The primary cardiovas- cular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocar- dial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. Secondary outcomes included all-cause mortality and the composite of the SPRINT primary outcome and all-cause mortality.

The primary renal disease outcome was assessed in par- ticipants with CKD at baseline (estimated glomerular filtra- tion rate [eGFR] <60 ml/min/1.73 m2 based on the 4-variable Modification of Diet in Renal Disease equation). It was based on the composite incidence of either a decrease in eGFR of 50% or greater (confirmed by subsequent laboratory test ≥90 days later) or the development of end-stage renal disease requir- ing long-term dialysis or transplantation. A secondary renal dis- ease outcome (assessed in participants without CKD at base- line) was based on incidence of a decrease in eGFR from 30% or greater at baseline to a value less than 60 mL/min/1.73 m2

(also confirmed by a subsequent test ≥90 days later).

Definition of Serious Adverse Events Serious adverse events (SAEs) were defined as events that were fatal or life threatening, resulted in signific ant or persistent disability, required hospitalization or resulted in prolonged hospitalization, or medical events that the investi- gator judged to be a significant hazard or harm to the partici- pant and required medical or surgical intervention to prevent any of these. The following conditions of interest were reported as adverse events if they were evaluated in an emer- gency department: hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia. Episodes of acute kidney injury (or acute renal failure) were monitored if they led to hospitalization and were reported in the hospital dis- charge summary.

Statistical Analysis Power to detect a 25% treatment effect for the primary out- come within the subgroup of participants aged 75 years or older was estimated assuming an enrollment of 3250. With a 2-year recruitment period, maximum follow-up of 6 years, and an- nual loss to follow-up of 2%, power was estimated to be 81.9%,

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assuming an event rate of 3.25% per year in the standard treat- ment group (Appendix B in Supplement 1).

Linear-mixed models with an unstructured covariance ma- trix, assuming independence across participants, were used to model longitudinal differences in SBP between treatment groups. Fixed effects in the model were BP at randomization and a treatment group indicator. The time to first occurrence of the primary composite outcome, all-cause mortality, pri- mary composite outcome plus all-cause mortality, SAEs, and loss to follow-up or withdrawing consent were compared be- tween the 2 randomized groups using Cox proportional haz- ards regression models with the baseline hazard function strati- fied by clinic site (participants were recruited at 100 clinics). Follow-up time was censored on the date of last event ascer- tainment on or before August 20, 2015, the date on which the

National Heart, Lung, and Blood Institute director decided to stop the intervention.

Exploratory secondary analyses were conducted to exam- ine modification of the treatment effect by frailty status and gait speed. Neither frailty status nor gait speed was a prespecified subgroup in the trial protocol. We fit separate Cox regression models for frailty status classified as fit (frailty index ≤0.10), less fit (frailty index >0.10 to ≤0.21), or frail (frailty index >0.21),16,17

and for gait speed classified as 0.8 m/s or greater (normal walker), less than 0.8 m/s (slow walker), or missing.18 Interactions be- tween treatment group, frailty status, and gait speed were for- mally tested by including interaction terms within a Cox regres- sion model (ie, using likelihood ratio tests to compare with a model that did not allow the treatment effect to vary by frailty status or gait speed). For the primary cardiovascular disease

Figure 1. Eligibility, Randomization, and Follow-up for Systolic Blood Pressure (SBP) Intervention Trial (SPRINT) Participants Aged 75 Years or Older

14 692 Assessed for eligibility 3756 Aged ≥75 y

9361 Randomized 2636 Aged ≥75 y

1317 Participants aged ≥75 y included in primary analysis 66 Did not complete gait speed

assessment at baseline 7 Frailty index could not be

computed at baseline

1319 Participants aged ≥75 y included in primary analysis 57 Did not complete gait speed

assessment at baseline 9 Frailty index could not be

computed at baseline

4678 Randomized to an SBP treatment target <120 mm Hg (intensive treatment) 1317 Aged ≥75 y

4683 Randomized to an SBP treatment target <140 mm Hg (standard treatment) 1319 Aged ≥75 y

All participants 224 Discontinued intervention 111 Were lost to follow-up 154 Withdrew consent

Participants aged ≥75 y 80 Discontinued intervention 26 Were lost to follow-up 36 Withdrew consent

All participants 242 Discontinued intervention 134 Were lost to follow-up 121 Withdrew consent

Participants aged ≥75 y 82 Discontinued intervention 31 Were lost to follow-up 33 Withdrew consent

5331 Ineligible or declined to participate

2284 Were taking too many medications or had SBP that was out of range a

718 Were not at increased cardiovascular risk b 703 Had miscellaneous reasons 587 Did not give consent

187 Had miscellaneous reasons 191 Did not give consent 155 Did not complete screening

653 Did not complete screening

Participants aged ≥75 y 1120 Ineligible or declined to participate

78 Had low SBP at 1 min after standing (<110 mm Hg)

509 Were taking too many medications or had SBP that was out of range a

34 Were <50 y of age 352 Had low SBP at 1 min

after standing (<110 mm Hg)

All participants

a Systolic blood pressure was required to be between 130 mm Hg and 180 mm Hg for participants taking 0 or 1 medication, 130 mm Hg to 170 mm Hg for participants taking 2 medications or fewer, 130 mm Hg to 160 mm Hg for participants taking 3 medications or fewer, and 130 mm Hg to 150 mm Hg for participants taking 4 medications or fewer.

b Increased cardiovascular risk was defined as presence of 1 or more of the following: (1) clinical or subclinical cardiovascular disease other than stroke, (2) chronic kidney disease (defined as an estimated glomerular filtration rate of 20 mL/min/1.73 m2 to 59 mL/min/1.73 m2 based on the 4-variable Modification of Diet in Renal Disease equation and the latest laboratory value within the past 6 months), (3) Framingham risk score for 10-year cardiovascular risk of 15% or greater based on laboratory work done within the past 12 months for lipids, or (4) age of 75 years or older.

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composite outcome, sensitivity analyses accounting for the com- peting risk of death were conducted using the subdistribution hazard model of Fine and Gray.19 All hypothesis tests were 2-sided at the 5% level of significance.

Additional analyses compared the total burden of SAEs be- tween the randomized groups (allowing for recurrent events) using the mean cumulative count estimator (standard errors computed using bootstrap resampling).20 Hazard ratios (HRs) were computed to compare the randomized groups using the gap-time formation of the Prentice, Williams, and Peterson re- current events regression model.21 All analyses were per- formed using SAS version 9.4 (SAS Institute Inc) and the R Sta- tistical Computing Environment (http://www.r-project.org).

Results

Baseline Characteristics and Study Retention Participants aged 75 years or older were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1319) (Figure 1). The treatment groups were similar for most characteristics with the exception of frailty status and aspirin use (Table 1). Overall, 815 partici- pants (30.9%) were classified as frail and 1456 (55.2%) as less fit (Table 1). A total of 2510 (95.2%) participants provided com- plete follow-up data.

Table 1. Baseline Characteristics of Participants Aged 75 Years or Older

Intensive Treatment (n = 1317)

Standard Treatment (n = 1319)

Female sex 499 (37.9) 501 (38.0)

Age, mean (SD), y 79.8 (3.9) 79.9 (4.1)

Race/ethnicity, No. (%)

White 977 (74.2) 987 (74.8)

Black 225 (17.1) 226 (17.1)

Hispanic 89 (6.8) 85 (6.4)

Other 26 (2.0) 21 (1.6)

Seated blood pressure, mean (SD), mm Hg

Systolic 141.6 (15.7) 141.6 (15.8)

Diastolic 71.5 (11.0) 70.9 (11.0)

Orthostatic hypotension, No. (%) 127 (9.6) 124 (9.4)

Serum creatinine, median (IQR), mg/dL 1.1 (0.9-1.3) 1.1 (0.9-1.3)

Estimated GFRa

Mean (SD), mL/min/1.73 m2 63.4 (18.2) 63.3 (18.3)

Level <60 mL/min/1.73 m2, No. (%) 584 (44.3) 577 (43.7)

Level <45 mL/min/1.73 m2, No. (%) 207 (15.7) 212 (16.1)

Urinary albumin to creatinine ratio, median (IQR), mg/g 13.0 (7.2-31.6) 13.4 (7.2-33.4)

History of cardiovascular disease, No. (%) 338 (25.7) 309 (23.4)

Total cholesterol, mean (SD), mg/dL 181.4 (39.0) 181.8 (38.7)

Fasting HDL cholesterol, mean (SD), mg/dL 55.9 (15.1) 55.7 (14.9)

Fasting total triglycerides, median (IQR), mg/dL 96.0 (71.0-130.0) 99.0 (72.0-134.5)

Fasting plasma glucose, mean (SD), mg/dL 97.9 (12.1) 98.2 (11.6)

Statin use, No. (%) 682 (51.8) 697 (52.8)

Aspirin use, No. (%) 820 (62.3) 765 (58.0)

10-y Framingham cardiovascular disease risk, median (IQR), %

24.2 (16.8-32.8) 25.0 (17.0-33.4)

Body mass index, mean (SD)b 27.8 (4.9) 27.7 (4.6)

No. of antihypertensive agents taking at baseline visit, mean (SD)

1.9 (1.0) 1.9 (1.0)

Gait speed

Median (IQR), m/s 0.90 (0.77-1.05) 0.92 (0.77-1.06)

Speed <0.8 m/s, No. (%) 371 (28.2) 369 (28.0)

Frailty index, median (IQR)c 0.18 (0.13-0.23) 0.17 (0.12-0.22)

Frailty status, No. (%)

Fit (frailty index ≤0.10) 159 (12.1) 190 (14.4)

Less fit (frailty index >0.10 to ≤0.21) 711 (54.0) 745 (56.5)

Frail (frailty index >0.21) 440 (33.4) 375 (28.4)

Montreal Cognitive Assessment score, median (IQR)d 22.0 (19.0-25.0) 22.0 (19.0-25.0)

Abbreviations: GFR, glomerular filtration rate; HDL, high-density lipoprotein; IQR, interquartile range.

SI conversion factors: To convert HDL and total cholesterol to mmol/L, multiply by 0.0259; triglycerides to mmol/L, multiply by 0.0113; and glucose to mmol/L, multiply by 0.0555. a Based on the 4-variable

Modification of Diet in Renal Disease equation.

b Calculated as weight in kilograms divided by height in meters squared.

c Scores range from 0 to 1, with higher values indicating greater frailty.

d Scores range from 0 to 30, with higher scores denoting better cognitive function.

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In the intensive treatment group, 440 participants (33.4%) were classified as frail compared with 375 participants (28.4%) in the standard treatment group. A total of 740 participants (28.1%) were classified as slow walkers (<0.8 m/s). There was no baseline treatment group difference in the proportion of par- ticipants classified as slow walkers or in performance on the Montreal Cognitive Assessment screening test.22

Even though participants who were less fit, frail, or with reduced gait speed exhibited higher rates of loss to follow-up or withdrawal of consent, there were no significant differ- ences between the treatment groups for frailty or low gait speed (eTable 1 in Supplement 2). The frequency at which partici- pants discontinued the intervention but continued follow-up was 6.2% in the intensive treatment group vs 6.4% in the stan- dard treatment group (P = .87).

Blood Pressure Levels Throughout follow-up, the mean SBP in the intensive treat- ment group was 123.4 mm Hg, and it was 134.8 mm Hg in the standard treatment group. The between-group difference in mean SBP was 11.4 mm Hg (95% CI, 10.8-11.9 mm Hg), which is a smaller relative difference than the mean SBP of 14.8 mm Hg observed in the trial overall (Table 2). Mean dia- stolic BPs during follow-up were 62.0 mm Hg in the inten- sive treatment group and 67.2 mm Hg in the standard treat- ment group.

On average, participants in the intensive treatment group required 1 more medication to reach the achieved

lower BP (eTable 2 and eFigure 1 in Supplement 2). Within the intensive treatment group, mean SBP during follow-up was higher for participants classified as less fit or frail com- pared with those considered fit. Differences in mean SBP by treatment group differed by frailty status (P = .01), with frail participants exhibiting smaller intertreatment group differ- ences (10.8 mm Hg) compared with less fit participants (11.3 mm Hg) and fit participants (13.5 mm Hg). Treatment group differences in SBP were similar across subgroups defined by gait speed.

Clinical Outcomes A primary composite outcome event was observed for 102 participants (2.59% per year) in the intensive treatment group and for 148 participants (3.85% per year) in the stan- d a rd t re at m e nt g ro u p ( H R , 0.6 6 [ 9 5% C I , 0. 5 1- 0.85 ] ; Table 3). Results were similar for all-cause mortality (there were 73 deaths in the intensive treatment group and 107 deaths in the standard treatment group; HR, 0.67 [95% CI, 0. 49 - 0.9 1 ] ) . I n f e r e n c e f o r t h e p r i m a r y o u t c o m e w a s unchanged when non–cardiovascular disease death was treated as a competing risk (HR, 0.66 [95% CI, 0.52-0.85]). At 3.14 years, the number needed to treat (NNT) estimate for the primary outcome was 27 (95% CI, 19-61) and for all- cause mortality it was 41 (95% CI, 27-145).

Bec ause the treatment effect estimate was not sta- tistically significant for cardiovascular disease death, the NNT estimate (using the abbreviations of Altman23) was an

Table 2. Least-Square Means for Postrandomization Blood Pressure Achieved by Treatment Group

Intensive Treatment Standard Treatment Difference Between Groups, Mean (95% CI)a

P Value for InteractionbNo. Mean (95% CI) No. Mean (95% CI)

Systolic blood pressure

Overall, mm Hg 1317 123.4 (123.0-123.9)c 1319 134.8 (134.3-135.2)c 11.4 (10.8-11.9)

Frailty statusd

Fit 159 121.4 (120.3-122.5) 190 134.9 (133.9-135.9) 13.5 (12.0-15.0)

.01Less fit 711 123.3 (122.8-123.9) 745 134.7 (134.1-135.2) 11.3 (10.6-12.1)

Frail 440 124.3 (123.5-125.0) 375 135.0 (134.2-135.8) 10.8 (9.7-11.8)

Gait speed

Speed ≥0.8 m/s 880 123.3 (122.8-123.8) 893 134.6 (134.0-135.1) 11.3 (10.6-11.9)

.67Speed <0.8 m/s 371 123.8 (123.0-124.6) 369 135.2 (134.4-136.0) 11.4 (10.4-12.5)

Missing 66 123.5 (121.7-125.2) 57 136.0 (134.0-137.9) 12.5 (9.9-15.1)

Diastolic blood pressure

Overall, mm Hg 1317 62.0 (61.7-62.3)c 1319 67.2 (66.8-67.5)c 5.2 (4.7-5.6)

Frailty statusd

Fit 159 61.9 (61.1-62.8) 190 67.4 (66.7-68.2) 5.5 (4.3-6.6)

.07Less fit 711 62.1 (61.7-62.6) 745 67.6 (67.2-68.0) 5.4 (4.9-6.0)

Frail 440 61.8 (61.3-62.3) 375 66.2 (65.6-66.8) 4.4 (3.6-5.1)

Gait speed

Speed ≥0.8 m/s 880 62.0 (61.6-62.3) 893 67.2 (66.9-67.6) 5.3 (4.8-5.8)

.08Speed <0.8 m/s 371 62.3 (61.7-62.8) 369 66.8 (66.2-67.4) 4.6 (3.8-5.4)

Missing 66 61.4 (60.1-62.7) 57 68.2 (66.7-69.6) 6.8 (4.8-8.8) a P < .001 for all mean differences. b From a mixed model. c Least-square means for blood pressure estimated from mixed model

conditioned on baseline blood pressure.

d Frailty status classified using 37-item frailty index (FI): fit (FI �0.10), less fit (FI >0.10 to �0.21), or frail (FI >0.21).

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NNTBenefit of 116 (NNTHarm of 544 to � to NNTBenefit of 68). In participants without CKD at the time of randomization, more participants in the intensive treatment group com- pared with the standard treatment group experienced the secondary CKD outcome (a 30% decrease in eGFR from baseline to an eGFR <60 mL/min/1.73 m2 [1.70% vs 0.58% per year, respectively]; HR, 3.14 [95% CI, 1.66-6.37]). There were no significant treatment group differences in the pri- mary renal outcome in those with baseline CKD; however, power to detect differences was limited due to low numbers of events.

Exploratory Subgroup Analyses Results stratified by baseline frailty status showed higher event rates with increasing frailty in both treatment groups (Table 4 and Figure 2). However, within each frailty stratum, absolute event rates were lower for the intensive treatment group (P = .84 for interaction). Results were similar when partici- pants were stratified by gait speed (P = .85 for interaction), with the HRs in favor of the intensive treatment group in each gait speed stratum (eFigure 2 in Supplement 2).

Serious Adverse Events Detailed information regarding SAEs appears in eTable 3 and eTable 4 in Supplement 2. Data on SAEs in participants older than 75 years have been previously reported (Table S613). In the intensive treatment group, SAEs occurred in 637 partici- pants (48.4%) compared with 637 participants (48.3%) in the standard treatment group (HR, 0.99 [95% CI, 0.89-1.11]; P = .90). The absolute rate of SAEs was higher but was not sta- tistically significantly different in the intensive treatment group for hypotension (2.4% vs 1.4% in the standard treatment group; HR, 1.71 [95% CI, 0.97-3.09]), syncope (3.0% vs 2.4%, respec- tively; HR, 1.23 [95% CI, 0.76-2.00]), electrolyte abnormali- ties (4.0% vs 2.7%; HR, 1.51 [95% CI, 0.99-2.33]), and acute kidney injury or renal failure (5.5% vs 4.0%; HR, 1.41 [95% CI, 0.98-2.04]). However, the absolute rate of injurious falls was lower but was not statistically significantly different in the in- tensive treatment group (4.9% vs 5.5% in the standard treat- ment group; HR, 0.91 [95% CI, 0.65-1.29]).

There was no statistically significant difference in the rate of orthostatic hypotension assessed during a clinic visit be- tween the treatment groups (21.0% in the intensive treat-

Table 3. Incidence of Cardiovascular, Renal, and Mortality Outcomes by Treatment Group

Intensive Treatment Standard Treatment

HR (95% CI)b P Value

No. With Outcome Events (n = 1317)a

% (95% CI) With Outcome Events/y

No. With Outcome Events (n = 1319)a

% (95% CI) With Outcome Events/y

All participants

Cardiovascular disease primary outcomec 102 2.59 (2.13-3.14) 148 3.85 (3.28-4.53) 0.66 (0.51-0.85) .001

Myocardial infarction (MI)d 37 0.92 (0.67-1.27) 53 1.34 (1.02-1.75) 0.69 (0.45-1.05) .09

ACS not resulting in MId 17 0.42 (0.26-0.68) 17 0.42 (0.26-0.68) 1.03 (0.52-2.04) .94

Stroked 27 0.67 (0.46-0.97) 34 0.85 (0.61-1.19) 0.72 (0.43-1.21) .22

Heart failured 35 0.86 (0.62-1.20) 56 1.41 (1.09-1.83) 0.62 (0.40-0.95) .03

Cardiovascular disease deathd 18 0.44 (0.28-0.70) 29 0.72 (0.50-1.03) 0.60 (0.33-1.09) .09

Nonfatal MI 37 0.92 (0.67-1.27) 53 1.34 (1.02-1.75) 0.69 (0.45-1.05) .09

Nonfatal stroke 25 0.62 (0.42-0.91) 33 0.83 (0.59-1.16) 0.68 (0.40-1.15) .15

Nonfatal heart failure 35 0.86 (0.62-1.20) 55 1.39 (1.06-1.81) 0.63 (0.40-0.96) .03

All-cause mortality 73 1.78 (1.41-2.24) 107 2.63 (2.17-3.18) 0.67 (0.49-0.91) .009

Primary outcome plus all-cause mortality 144 3.64 (3.09-4.29) 205 5.31 (4.63-6.09) 0.68 (0.54-0.84) <.001

CKD

Primary CKD outcomee 7/584 0.38 (0.18-0.81) 4/577 0.23 (0.08-0.60) 1.68 (0.49-6.59) .42

Incident albuminuriaf 26/196 4.43 (3.02-6.51) 28/177 5.56 (3.84-8.06) 0.96 (0.53-1.75) .90

Non-CKD

Secondary CKD outcomeg 37/726 1.70 (1.23-2.35) 13/732 0.58 (0.34-1.01) 3.14 (1.66-6.37) <.001

Incident albuminuriaf 29/303 3.31 (2.30-4.76) 42/304 4.84 (3.58-6.55) 0.80 (0.46-1.35) .40

Abbreviations: ACS, acute coronary syndrome; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IQR, interquartile range. a The total No. of participants is provided if it is different from treatment

group total. b Intensive treatment group vs standard treatment group. c Includes nonfatal myocardial infarction, acute coronary syndrome not

resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. Median follow-up time for the intensive treatment group was 3.16 years (IQR, 2.63-3.70 years), with 3938.2 person-years of follow-up. In the standard treatment group, median follow-up time was 3.12 years (IQR, 2.67-3.67 years), with 3841.0 person-years of follow-up.

d These rows do not sum to the cardiovascular disease primary outcome. Only the first event contributes to the primary outcome, whereas participants with multiple events could contribute to each component outcome.

e Includes a 50% reduction in eGFR (measured twice at least 90 days apart), dialysis, or a kidney transplant.

f Only applies to participants with urinary albumin to creatinine ratio of less than 10 mg/g at baseline, and required a doubling of the urinary albumin to creatinine ratio from less than 10 mg/g to 10 mg/g or greater (measured twice at least 90 days apart).

g Includes a 30% reduction in eGFR (measured twice at least 90 days apart) to an eGFR of less than 60 mL/min/1.73 m2, dialysis, or a kidney transplant.

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ment group vs 21.8% in the standard treatment group; HR, 0.90 [95% CI, 0.76-1.07]); however, the absolute rate of ortho- static hypotension in combination with a report of dizziness was higher but was not statistically significantly different in the intensive treatment group (1.9% vs 1.3% in the standard treatment group; HR, 1.44 [95% CI, 0.77-2.73]). Even though the SAE rates were higher with greater frailty or slower walk- ing speed, these rates were not statistically different by treat- ment group when stratified by frailty status or gait speed.

Discussion These results extend and detail the main SPRINT study find- ings in community-dwelling persons aged 75 years or older, demonstrating that a treatment goal for SBP of less than 120 mm Hg reduced incident cardiovascular disease by 33% (from 3.85% to 2.59% per year) and total mortality by 32% (from 2.63% to 1.78% per year).13 Translating these findings into num- bers needed to treat suggests that a strategy of intensive BP control for 3.14 years would be expected to prevent 1 primary outcome event for every 27 persons treated and 1 death from any cause for every 41 persons treated. These estimates are lower than those from the overall results of the trial due to the higher event rate in persons aged 75 years or older. In addi-

tion, exploratory analysis suggested that the benefit of inten- sive BP control was consistent among persons in this age range who were frail or had reduced gait speed.

The overall SAE rate was comparable by treatment group, including among the most frail participants. There were no dif- ferences in the number of participants experiencing injuri- ous falls or in the prevalence of orthostatic hypotension mea- sured at study visits. These results complement results from other trials demonstrating improved BP control reduces risk for orthostatic hypotension and has no effect on risk for inju- rious falls.24-26 The numbers of participants aged 75 years or older who dropped out of the study, were lost to follow-up, or decided to discontinue the intervention but continued with outcome assessment were low and did not differ by treat- ment group.

There are several limitations to these results from SPRINT involving participants aged 75 years or older. Even though the trial was designed to enhance recruitment of a prespecified sub- group of adults aged 75 years or older, randomization in SPRINT was not stratified by categories of age. In addition, the trial did not enroll older adults residing in nursing homes, persons with type 2 diabetes or prevalent stroke (because of concurrent BP lowering trials),27,28 and individuals with symptomatic heart failure due to protocol differences required to maintain BP con- trol in this condition. Therefore, the results reported in this

Table 4. Incidence of Cardiovascular and Mortality Outcomes by Frailty Status and Gait Speed

Intensive Treatment Standard Treatment

HR (95% CI)a P Value P Value for Interaction

No./Total With Outcome Events

% (95% CI) With Outcome Events/y

No./Total With Outcome Events

% (95% CI) With Outcome Events/y

Frailty statusb

Primary outcomec Fit 4/159 0.80 (0.30-2.12) 10/190 1.72 (0.93-3.20) 0.47 (0.13-1.39)d .20

.84Less fit 48/711 2.23 (1.68-2.97) 77/745 3.51 (2.81-4.39) 0.63 (0.43-0.91) .01

Frail 50/440 3.90 (2.96-5.15) 61/375 5.80 (4.52-7.46) 0.68 (0.45-1.01) .06

All-cause mortality

Fit 5/159 0.98 (0.41-2.36) 6/190 1.01 (0.45-2.24) 0.95 (0.27-3.15)d .93

.52Less fit 26/711 1.16 (0.79-1.71) 52/745 2.24 (1.71-2.95) 0.48 (0.29-0.78) .003

Frail 40/440 2.95 (2.17-4.03) 49/375 4.28 (3.24-5.67) 0.64 (0.41-1.01) .05

Primary outcome plus all-cause mortalityc

Fit 8/159 1.59 (0.80-3.19) 13/190 2.24 (1.30-3.86) 0.71 (0.28-1.69)d .45

.88Less fit 65/711 3.01 (2.36-3.84) 108/745 4.90 (4.05-5.91) 0.60 (0.44-0.83) .002

Frail 69/440 5.37 (4.24-6.80) 84/375 7.95 (6.42-9.85) 0.67 (0.48-0.95) .02

Gait speed

Primary outcomec Speed ≥0.8 m/s 59/880 2.22 (1.72-2.87) 86/893 3.24 (2.63-4.01) 0.67 (0.47-0.94) .02

.85Speed <0.8 m/s 34/371 3.15 (2.25-4.41) 54/369 5.22 (4.00-6.81) 0.63 (0.40-0.99) .05

Missing 9/66 4.40 (2.29-8.46) 8/57 5.13 (2.57-10.27) 0.86 (0.33-2.29)d .75

All-cause mortality

Speed ≥0.8 m/s 40/880 1.45 (1.07-1.98) 60/893 2.16 (1.67-2.78) 0.65 (0.43-0.98) .04

.68Speed <0.8 m/s 29/371 2.56 (1.78-3.68) 40/369 3.57 (2.62-4.86) 0.75 (0.44-1.26) .28

Missing 4/66 1.85 (0.69-4.93) 7/57 4.19 (2.00-8.80) 0.44 (0.12-1.47)d .20

Primary outcome plus all-cause mortalityc

Speed ≥0.8 m/s 82/880 3.08 (2.48-3.83) 119/893 4.48 (3.74-5.36) 0.67 (0.50-0.89) .006

.91Speed <0.8 m/s 51/371 4.70 (3.57-6.18) 73/369 7.00 (5.56-8.80) 0.69 (0.46-1.01) .06

Missing 11/66 5.37 (2.97-9.70) 13/57 8.30 (4.82-14.30) 0.64 (0.28-1.44)d .28

Abbreviation: HR, hazard ratio. a Intensive treatment group vs standard treatment group from Cox proportional

hazards regression model with baseline hazard stratified by clinic site. b Classified using a 37-item frailty index (FI): fit (FI �0.10), less fit (FI >0.10 to

�0.21), or frail (FI >0.21).

c Primary outcome includes nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes.

d Due to small sample size, HR estimated from Cox model assuming common baseline hazard across clinic site.

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study among persons aged 75 years or older do not provide evi- dence regarding treatment targets in these populations. Indi- viduals with these conditions also represent a subset of older persons at increased risk for falls.

No other chronic conditions were excluded from this trial, and the frailty index applied in this study combined with the assessment of gait speed contribute to assessing possible ef- fect modification by comorbidity and functional status. In ex- ploratory analyses, there was no evidence of heterogeneity for

the cardiovascular benefit of intensive BP management by frailty or gait speed. However, these analyses should be inter- preted cautiously. The analyses were not prespecified in the trial protocol and were possibly underpowered because SPRINT was designed to consider only the ability to detect a treat- ment effect in participants aged 75 years or older as a whole.

Despite excluding some chronic conditions, 30.9% of par- ticipants aged 75 years or older in this trial were categorized as frail at baseline, and the distribution of frailty status paral- lels that estimated for ambulatory, community living popula- tions of similar age.15 In addition, the proportion of US adults aged 75 years or older who have hypertension and meet the study entry criteria has been estimated to represent 64% of that population using the 2007-2012 National Health and Nutri- tion Surveys (approximately 5.8 million individuals).29 There- fore, participants aged 75 years or older in this trial are repre- sentative of a sizeable fraction of adults in this age group with hypertension.

There are several important comparisons to make with HYVET,30 which randomized 3845 patients aged 80 years or older within Europe and Asia (mean age, 83 years [3 years older than SPRINT]; mean entry SBP, 173 mm Hg [31 mm Hg higher than SPRINT]) to either therapy with indapamide, with or with- out the angiotensin-converting enzyme inhibitor perindo- pril, or placebo with an SBP treatment goal of less than 150 mm Hg. The 2-year between-group SBP difference was 15 mm Hg (the active treatment group achieved a mean SBP of 143 mm Hg, slightly higher than the SPRINT baseline SBP). Similar to SPRINT, HYVET was terminated early (at a median follow-up time of 1.8 years) due to significant reductions in the incidence rate of total mortality. A retrospective analysis of the HYVET population conducted to determine its frailty status identified that (1) the cohort’s frailty status was similar to that of community living populations of similar age and (2) the treat- ment benefits were similar even in the most frail participants.12

Taken together, current results from SPRINT also reinforce and extend HYVET’s conclusions that risk reductions in cardio- vascular disease events and mortality from high BP treat- ment are evident regardless of frailty status.

Among all participants aged 75 years or older, the SAEs re- lated to acute kidney injury occurred more frequently in the intensive treatment group (72 participants [5.5%] vs 53 par- ticipants [4.0%] in the standard treatment group). The differ- ences in adverse renal outcomes may be related to a revers- ible intrarenal hemodynamic effect of the reduction in BP and more frequent use of diuretics, angiotensin-converting en- zyme inhibitors, and angiotensin II receptor blockers in the in- tensive treatment group.31,32 Although there is no evidence of permanent kidney injury associated with the lower BP goal, the possibility of long-term adverse renal outcomes cannot be excluded and requires longer-term follow-up.

Considering the high prevalence of hypertension among older persons, patients and their physicians may be inclined to underestimate the burden of hypertension or the benefits of lowering BP, resulting in undertreatment. On average, the benefits that resulted from intensive therapy required treat- ment with 1 additional antihypertensive drug and additional early visits for dose titration and monitoring. Future analyses

Figure 2. Kaplan-Meier Curves for the Primary Cardiovascular Disease Outcome in Systolic Blood Pressure Intervention Trial (SPRINT) in Participants Aged 75 Years or Older by Baseline Frailty Status

0.4

0.3

0.2

0.1

0 0

190 159

1

186 151

2

182 150

3

94 107

4

19 16

5

Cu m

ul at

iv e

H az

ar d

Fit (FI ≤0.10)

Years No. at risk

Type of treatment Standard Intensive

HR, 0.47 (95% CI, 0.13-1.39); Cox regression P = .20

Standard treatment Intensive treatment

No. at risk Type of treatment

Standard Intensive

Standard treatment

Intensive treatment

0.4

0.3

0.2

0.1

0 0

745 711

1

697 677

2

653 644

3

390 378

4

91 93

5

Cu m

ul at

iv e

H az

ar d

Less fit (FI >0.10 to ≤0.21)

Years

HR, 0.63 (95% CI, 0.43-0.91); Cox regression P = .01

No. at risk Type of treatment

Standard Intensive

Standard treatment

Intensive treatment

0.4

0.3

0.2

0.1

0 0

375 440

1

338 398

2

305 371

3

177 223

4

49 71

5

Cu m

ul at

iv e

H az

ar d

Frail (FI >0.21)

Years

HR, 0.68 (95% CI, 0.45-1.01); Cox regression P = .06

Tinted regions indicate 95% confidence intervals; FI, 37-item frailty index; HR, hazard ratio. The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes.

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of SPRINT data may be helpful to better define the burden, costs, and benefits of intensive BP control. However, the present results have substantial implications for the future of intensive BP therapy in older adults because of this condi- tion’s high prevalence, the high absolute risk for cardiovascu- lar disease complications from elevated BP, and the devastat- ing consequences of such events on the independent function of older people.3,29,33,34

Conclusions

Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause.

ARTICLE INFORMATION

Published Online: May 19, 2016. doi:10.1001/jama.2016.7050.

Author Affiliations: Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Department of Internal Medicine, Winston-Salem, North Carolina (Williamson, Applegate, Sink, Woolard); Division of Geriatrics, School of Medicine, University of Utah, Salt Lake City (Supiano); Veterans Affairs Salt Lake City, Geriatric Research, Education, and Clinical Center, Salt Lake City, Utah (Supiano); Bedford Veterans Affairs Hospital, Bedford, Massachusetts (Berlowitz); School of Public Health, Boston University, Boston, Massachusetts (Berlowitz); Department of Medicine, Medical University of South Carolina, Charleston (Campbell); Department of Medicine, Stanford University School of Medicine, Palo Alto, California (Chertow); Clinical Applications and Prevention Branch, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland (Fine); Department of Nephrology and Hypertension, Mayo Clinic, Jacksonville, Florida (Haley); Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina (Hawfield); Division of Nephrology and Hypertension, Department of Medicine, University of California, San Diego (Ix); Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California, San Diego (Ix); Department of Medicine, Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, California (Ix); Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Kitzman); Cardiovascular Institute at Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey (Kostis); Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana (Krousel-Wood); Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana (Krousel-Wood); Center for Applied Health Research, Ochsner Clinic Foundation, New Orleans, Louisiana (Krousel-Wood); Intramural Research Program, National Institute on Aging, Bethesda, Maryland (Launer); Division of Cardiovascular Disease, Department of Medicine, University of Alabama, Birmingham (Oparil); Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina (Rodriguez); Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, HSR&D Center, Nashville (Roumie); Department of Medicine, Vanderbilt University, Nashville, Tennessee (Roumie); Department of Epidemiology, University of Florida, Gainesville (Shorr); Geriatric Research, Education, and Clinical Center, Malcom Randall Veterans Administration

Medical Center, Gainesville, Florida (Shorr); Department of Medicine, University of Alabama, Birmingham (Wadley); Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana (Whelton); Department of Medicine, Medical College of Wisconsin, Milwaukee (Whittle); Primary Care Division, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin (Whittle); Division of Nephrology and Hypertension, Department of Medicine, Case Western Reserve University, Cleveland, Ohio (Wright); Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina (Pajewski).

Author Contributions: Dr Pajewski had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Williamson, Supiano, Applegate, Berlowitz, Chertow, Fine, Kitzman, Launer, Rodriguez, Shorr, Sink, Wadley, Whelton, Wright, Pajewski. Acquisition, analysis, or interpretation of data: Williamson, Supiano, Applegate, Berlowitz, Campbell, Chertow, Fine, Haley, Hawfield, Ix, Kostis, Krousel-Wood, Oparil, Rodriguez, Roumie, Shorr, Sink, Whelton, Whittle, Woolard, Wright, Pajewski. Drafting of the manuscript: Williamson, Supiano, Applegate, Shorr, Wright, Pajewski. Critical revision of the manuscript for important intellectual content: Williamson, Supiano, Applegate, Berlowitz, Campbell, Chertow, Fine, Haley, Hawfield, Ix, Kitzman, Kostis, Krousel-Wood, Launer, Oparil, Rodriguez, Roumie, Sink, Wadley, Whelton, Whittle, Woolard, Wright, Pajewski. Statistical analysis: Pajewski. Obtained funding: Williamson, Chertow, Fine, Kitzman, Oparil, Wright. Administrative, technical, or material support: Williamson, Campbell, Ix, Kitzman, Kostis, Oparil, Roumie, Whelton, Woolard, Wright. Study supervision: Williamson, Applegate, Berlowitz, Fine, Kitzman, Oparil, Wadley, Whelton, Wright.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Williamson reported receiving nonfinancial support from Takeda Pharmaceuticals and Arbor Pharmaceuticals during the conduct of the study. Dr Kitzman reported receiving personal fees from Merck, Forest Labs, and Abbvie; personal fees and other from Gilead and Relypsa; and grants from Novartis outside the submitted work. Dr Oparil reported receiving personal fees from Forest Laboratories Inc; grants, personal fees, and nonfinancial support from Medtronic; personal fees from Amgen (Onyx is subsidiary); grants and personal fees from AstraZeneca and Bayer

Healthcare Pharmaceuticals Inc; personal fees from Boehringer-Ingelheim and GlaxoSmithKline; grants from Merck and Co; and serving as co-chair for the Eighth Joint National Committee. No other disclosures were reported.

Funding/Support: The SPRINT study was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke) under contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200900049C and interagency agreement A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. Azilsartan and chlorthalidone (combined with azilsartan) were provided by Takeda Pharmaceuticals International Inc. Additional support was provided by grants P30-AG21332 and R01-HL10741 from the Wake Forest Claude Pepper Older Americans Independence Center; through the following National Center for Advancing Translational Sciences clinical and translational science awards: UL1TR000439 (awarded to Case Western Reserve University); UL1RR025755 (Ohio State University); UL1RR024134 and UL1TR000003 (University of Pennsylvania); UL1RR025771 (Boston University); UL1TR000093 (Stanford University); UL1RR025752, UL1TR000073, and UL1TR001064 (Tufts University); UL1TR000050 (University of Illinois); UL1TR000005 (University of Pittsburgh); 9U54TR000017-06 (University of Texas Southwestern Medical Center); UL1TR000105-05 (University of Utah); UL1 TR000445 (Vanderbilt University); UL1TR000075 (George Washington University); UL1 TR000002 (University of California, Davis); UL1 TR000064 (University of Florida); and UL1TR000433 (University of Michigan); and by National Institute of General Medical Sciences, Centers of Biomedical Research Excellence award NIGMS P30GM103337 (awarded to Tulane University).

Role of the Funder/Sponsor: The SPRINT steering committee was responsible for the design and conduct of the study, including the collection and management of the data. Scientists at the National Institutes of Health as a group and the principal investigator of the Veterans Affairs clinical network had 1 vote on the steering committee of the trial. There were 7 voting members of the steering committee. The National Institutes of Health, the US Department of Veterans Affairs, and the US government had no role in analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Intensive Blood Pressure Control in Adults Aged 75 Years or Older Original Investigation Research

jama.com (Reprinted) JAMA June 28, 2016 Volume 315, Number 24 2681

Copyright 2016 American Medical Association. All rights reserved.

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Group Information: The members of the SPRINT Research Group have been published elsewhere.13

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the US Department of Veterans Affairs, or the US government.

Previous Presentation: Presented in part at the Gerontological Society of America annual meeting; November 21, 2015; Orlando, Florida.

Additional Contributions: We thank Sarah Hutchens and Pamela Nance, BA (both with the Wake Forest School of Medicine), for their assistance in preparation of the manuscript, for which neither received any compensation.

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