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Anticholinergic medi- alternative explanations for treatment effects caverta 100mg without a prescription erectile dysfunction treatment options natural. For the most cations given for extrapyramidal side effects compromise part buy caverta 100mg otc diabetic erectile dysfunction icd 9 code, studies have not been designed or analyzed in a way certain neurocognitive abilities buy caverta 50 mg free shipping erectile dysfunction causes in early 20s. Although the range of ef- that allows one to rule out indirect effects generic caverta 100mg with visa impotence word meaning. For example, if fects of anticholinergic medications is not well character- a newer antipsychotic medication has a better clinical effect ized, they may disrupt aspects of secondary verbal memory than a conventional medication, it may improve neurocog- that rely on rehearsal strategies (18). Other aspects of mem- nition as an indirect benefit of greater symptom reduction. Sev- less affected (4,38), and the effects on other neurocognitive eral studies have noted that changes in neurocognition ap- abilities, such as visual processing, are relatively unknown. An alternative explanation is that the neuro- appears to be more promising. Initial interest in the neuro- cognitive benefits of newer medications are mediated by a cognitive effects of new antipsychotic medications was stim- reduced need for anticholinergic medications. Although this ulated by a series of (mainly open-label) studies of clozapine may turn out be true in some instances, the differential use (4,38,47,53,67). The results of these studies were surprising of anticholinergic medications did not explain the effects in two respects: First, in most of the studies, clozapine treat- of risperidone on immediate and secondary verbal memory ment resulted in improvement in verbal fluency (i. The beneficial effects of newer medi- ability to generate words that begin with a certain letter or cations on neurocognition may be mediated by lower rates belong to a certain semantic category) and possibly psycho- of extrapyramidal symptoms. Second, the initiation of clozapine treatment effects will be seen in comparisons with very low doses of in some studies appeared to have at least short-term detri- conventional medications, when side effects are minimal. These studies (again, mostly transient D2 blockade remains a viable explanation of open-label) have generally shown that they have benefits for 'atypicality' (59). Thus, it is possible that the administra- neurocognition in comparison with conventional antipsy- tion of conventional neuroleptics in inappropriately high chotic medications. Indications of short-term detrimental doses resulted in a lack of improvement, although dose- effects, similar to those seen in some clozapine studies, have reduction studies do not support this explanation (93,97). A rather comprehensive review (72) and a met- mains obscure. In any event, a single neurotransmitter effect aanalysis (61) of the existing literature have both provided seems unlikely to account for the effects, which probably a basis for optimism about the beneficial neurocognitive involve a constellation of actions at serotonergic, adrenergic, effects of newer medications. The metaanalysis of Keefe et cholinergic, and dopaminergic receptors (72). The neuropsychological signature of cholinergic medications). Am J Psychiatry These medications were not developed or initially evaluated 1994;151:40–48. The generalized pattern of neuropsychological deficits in outpatients with chronic schizo- tive pharmacology specifically for neurocognitive deficits is phrenia with heterogeneous Wisconsin Card Sorting Test re- now receiving serious consideration. A key challenge for directing studies of adjunctive noso- 3. Effect of antipsychotic medication on tropic medications in schizophrenia is deciding which neu- speed of information processing in schizophrenic patients. The comparative efficacy ogy of neurocognitive deficits in schizophrenia. One that and long-term effect of clozapine treatment on neuropsycho- has been implicated is the glutamate system (78). N-methyl-D-aspartate (NMDA) subtype of glutamate re- 6. Neuropsychological functioning in siblings discordant for schizophrenia and healthy ceptor, such as phencyclidine and ketamine, it has been volunteers. Because the NMDA receptor is modu- on neuropsychological function in chronic schizophrenic pa- lated by glycine, glycinergic agents can provide a useful tients. Neuropsychological means for manipulating glutamate function. Glycine itself evidence supporting a neurodevelopmental model of schizo- has been utilized by Javitt et al. Sustained attention deficit partial glycine agonist, resulted in a benefit in choice reac- and schizotypal personality features in nonpsychotic relatives of tion time when it was utilized in conjunction with conven- schizophrenic patients. Verbal working mem- tional antipsychotic medications (32), but not when added ory impairment in schizophrenia patients and their first-degree to clozapine (33). A full glycine agonist, D-serine, demon- relatives: evidence from the digit span task. Am J Psychiatry strated some success in improving WCST performance 2000;157:275–277. If these studies of adjunctive agents result in reliable 11. Psychiatr Q 1997;68: improvement in neurocognition in schizophrenia, it may 343–359. Functional mechanisms under- cation for each of the major domains of illness, clinical lying impaired recognition memory and conscious awareness symptoms and neurocognitive deficits. IQ and risk for schizo- phrenia: a population-based cohort study. Severity of symp- toms in chronically institutionalized geriatric schizophrenic pa- tients. In the lay imagination, schizophrenic patients experience 15. Behavioral selves, out of touch with reality, and disorganized. The view and intellectual markers for schizophrenia in apparently healthy of scientists, once not altogether different, has changed. Neurocognitive defi- cits and social functioning in outpatients with schizophrenia. Human memory and the cholinergic impairments may be a relatively central feature of the disor- system. Cognitive impairments are involved in the genetic etiol- 19. Relative risk of attention deficits in siblings of patients with schizophrenia. They seem enduring in that they are J Psychiatry 2000;157:1309–1316. Cognitive impairments also may have a rela- cognitive impairments in siblings of patients with schizophrenia tively well-delineated profile in which executive, memory, Biol Psych 2001;50:98–107. Neuropsychological ments should be considered target symptoms in the same evidence for frontostriatal dysfunction in schizophrenia. Psychol way as hallucinations, delusions, and anergia. Chapter 48: Neurocognitive Functioning in Patients with Schizophrenia 667 22. The use of cognitive and functional outcome in schizophrenia: are we measuring the context in schizophrenia: an investigation. Continuous perfor- performances in unaffected siblings of schizophrenic patients. Arch Gen Psychiatry 1997; patibility, working memory, response readiness, or none of the 54:465–472. Neuropsychologi- tive functions and psychiatric symptoms in treatment-refractory cal functioning among the nonpsychotic relatives of schizo- schizophrenic patients receiving clozapine. Biol Psychiatry 1993; phrenic patients: a diagnostic efficiency analysis.
G Some alcohol-dependent men and women have high cor- proteins come in several forms that either stimulate (G )os r tisol 50 mg caverta free shipping erectile dysfunction over 65, and children of alcoholics have a differential hormonal inhibit (G )I the process purchase 50 mg caverta erectile dysfunction pump walgreens. Although there is some evidence that re- stimulate G buy generic caverta 100mg on-line erectile dysfunction causes pdf. Recently detoxified alcoholics and their nonal-s covering alcoholics and children of alcoholics show lower coholic relatives might have lower cAMP production fol- levels of HPA response to alcohol generic 50mg caverta otc erectile dysfunction onset, these same groups might lowing chemical stimulation of platelets or white blood cells, show higher levels of response to naltrexone, an opioid an- results that have been hypothesized to be related to a re- tagonist (67–69). However, AC activity is also The functioning of the HPA axis is at least partially under affected by drinking and by withdrawal, and differences genetic control (70). Thus, activity of this system might from controls can change depending on periods of absti- contribute to the alcoholism risk, perhaps indirectly through nence or following the production of multiple generations several channels described in other sections. In the final analysis, differences between alcoholics and controls are probably both state and trait phenomena. Other Potentially Interesting Broad Phenotypes Regarding the latter, activity of the system appears to be Additional phenomena, including other personality disor- genetically influenced, and it is possible the divergence in ders (e. The production of functioning), and other psychiatric syndromes [e. Thus, reflecting space constraints, this discussion is not One theory attempting to integrate these findings is that exhaustive and the reader should consider additional review an avenue of alcoholism risk might be a low innate activity papers. The underlying differ- Potentially Related to the Alcoholism ence has been hypothesized to involve a reduction of gene Risk expression of the subunit of the Gs protein (72). The process might have an impact on the development of toler- This subsection highlights some specific genes, enzymes, ance, and, perhaps, the need for higher levels of alcohol to and other proteins that might relate to an alcoholism vulner- have an effect. The distinction between broad potential phenotypic regarding the role of alcohol in decreasing neuronal excita- markers of alcoholism (discussed above) and the more spe- bility through enhancing G-protein–coupled inwardly rec- cific markers noted here is somewhat arbitrary, but might tifying potassium channels (GIRKs) (78). Adenylyl Cyclase (AC) and G Proteins These proteins include three membrane-bound components Protein Kinase C (PKC) of receptors, G (or guanine nucleotide binding) proteins, and the AC enzyme that are part of a complex second mes- These proteins encompass at least three families of enzymes senger system that translates the impact of alcohol, neuro- that, similar to AC, have important functions in translating transmitters, and other substances on the cell membrane or the effects of neurotransmitters on receptors into the cell. The G pro- These calcium-activated, phospholipid-dependent proteins teins facilitate the coupling of at least nine different isoforms are widely distributed in the body, and function by phos- Chapter 98: Vulnerability Factors for Alcoholism 1403 phorylating target proteins, including G proteins, and thus, Opioid-Like Substances, Including -Endorphin mediating changes in intracellular signaling (81,82). The opioids are endogenous proteins, including endorphins The direction of the impact of alcohol on PKC activity and enkephalins, as well as most of the prescription pain can be different with acute versus chronic administration, medications, methadone, heroin, codeine, and morphine, but in general ethanol affects the movement of this protein each of which bind to opioid receptors. Their actions dimin- from the area around the nucleus to the cytoplasm (83). The ish pain, decrease respirations, cause euphoria, and produce changes in PKC subsequently have impact on the actions a decreased motility in the gut. There are a variety of opioid of several neurotransmitter receptors, including 5-HT and receptor subtypes including , , and , with most closely GABAA, and thus, are likely to affect alcohol intoxication tied to analgesic and reinforcing effects (91). Aspects Although no data are yet available in children of alcoholics, of tolerance and withdrawal from alcohol might relate to mice genetically engineered for an absence of PKC- have changes in functioning of the receptors, and alcohol-pre- both a high sensitivity to alcohol and lower self-administra- ferring animals have an increase in these receptors in the tion of this drug (82). Such animals also show a decreased ventral tegmentum, along with a greater increase in -en- reaction to pain, perhaps reflecting changes in opioid activ- dorphin following alcohol (94–96). There is additional evidence that PKC- knockout response to naltrexone (an opioid antagonist) has been re- mice have a lower intensity of reaction to alcohol, and less ported in alcoholics and their relatives, perhaps reflecting ability to develop tolerance to at least some effects of the less baseline opioid functioning (97). Opioid antagonists, such as naltrexone and nalmephene, can de- NPY is a widely distributed neurotransmitter that affects crease the self-administration of alcohol in animals and hu- multiple receptor subtypes including Y1 (in the amygdala mans, perhaps by blunting the stimulatory effect of alcohol, where NPY decreases feelings of anxiety), and Y5 (in the enhancing the sedative effects of this drug, and/or through hypothalamus where NPY might increase appetitive behav- decreased levels of reinforcement from alcohol (93,97,98). NPY appears to act through G proteins, pro- A opioid receptor gene might be located near a QTL ducing an inhibition of AC production, and this transmitter for alcohol preference in mice (99), and there is a possible can facilitate the release of DA in the nucleus accumbens association between alcoholism and some of the six more (86). It has been hypothesized to play a role in eating disor- known alleles of the opioid receptor (OPRM1), although ders, depression, anxiety, and the actions of opioids (87). Acute alcohol intake has impact on NPY release, which in turn affects the release of DA, possibly contributing to some rewarding effects of alcohol or adding to some psychi- The Serotonin (5-HT) Systems atric symptoms (85,86,88). Chronic alcohol intake and withdrawal are associated with increased NPY in the hypo- The actions of this neurotransmitter, which are mediated thalamus, and increased responsiveness of CRF to NPY through the 5-HT transporter (5-HTT) and more than 14 (85). Numerous drugs of abuse have impact on 5-HT sys- third of the enhanced alcohol intake, and which is located tems, including alcohol, and 5-HT, in turn, also interacts in an area where NPY has been mapped (89). In addition, with other neurotransmitters, especially DA (6). The follow- rats bred to consume high levels of alcohol have increased ing data suggest that different genes affecting 5-HT levels NPY activity in the amygdala (perhaps reflecting levels of could increase the alcoholism risk through several different anxiety), along with decreased NPY in the frontal cortex mechanisms. Mice genetically engineered for an absence of NPY perhaps, feelings of craving (101). Alcoholics, especially drink more alcohol and have a lower intensity of response those with aggressiveness or an early onset of their substance compared to wild-type mice, whereas transgenetic mice with use disorder, may have lower levels of platelet and brain 5- increased NPY have less alcohol consumption and higher HT, diminished responses to 5-HT boosting drugs, and responses to alcohol (79,90). Studies have not yet been car- lower levels of 5-HT metabolites in the CSF (6,102). These findings have led to a search for specific DA mark- Alcohol preference in animals is associated with a QTL ers possibly tied to a vulnerability toward alcoholism. The s-allele decrease in the D2 receptor density has been reported in may relate to nervousness, harm avoidance, and other forms the brain of alcohol-preferring rodents and some alcoholics, of anxiety that might tie in to axis I anxiety disorders and as has a blunted hormonal response to D2 agonists, at least more severe alcohol withdrawal, although not all authors soon after withdrawal (115,116). The l-allele, which might produce a protein synapse might result from a higher density of DA uptake that more rapidly takes up 5-HT from the synapse, has been as seen in alcohol-preferring primates, although possibly re- tied to a low LR to alcohol and an enhanced alcoholism flecting withdrawal, the opposite was reported in the stria- risk (32). Another gene that controls the production of the tum in a small sample of nonviolent alcoholics (116,117). However, results relating to this candidate higher alcohol intake either directly or through ASPD, de- have not been replicated in genome scans, and there are as pressive disorders, schizophrenia, or anxiety disorders. Find- many nonconfirmatory studies as there are positive ones (6, ings include a high receptor density for 5-HT1Aor a decrease 119). Additional interest has been expressed regarding the in 5-HT1B activity in alcohol-preferring rats, with 5-HT1B D4 receptor and several alleles of the DA transporter, but knockout mice demonstrating higher levels of alcohol intake with conflicting results (120,121). Turning to a second family of receptors, there is evidence of a decrease in 5-HT2C receptor sensitivity in GABA, Norepinephrine (NE), and Monoamine alcoholics, along with a potential increase in the density of Oxidase (MAO) these proteins in the hippocampus in alcohol-preferring rats This subsection briefly reviews several markers that might (108). A third family has also been implicated through the relate to the alcoholism risk. GABA, a ubiquitous inhibitory actions of the 5-HT3 receptor, which promotes the release neurotransmitter, has an important role in several condi- of dopamine in the nucleus accumbens in the context of tions possibly related to the alcoholism risk including anxi- alcohol (6,109). There are multiple GABA receptors, with special 5-HT in platelets, perhaps indicating a lower level of 5- interest for alcohol intoxication or withdrawal for the esti- HT in the synapse that might relate to LR (110). This is mated 13 or more subunits for the GABA receptor com- A consistent with lower LR to alcohol in the offspring who plex (6,32,122). Alcohol-dependent men and women have have the l-allele of the 5-HTT (32). Finally, a drug that a decreased density of GABA receptors, and might show A antagonizes activity of the 5-HT3receptor, ondansetron, decreased responses to lorazepam in frontal brain regions both decreases subjective feelings of intoxication with alco- and in the basal ganglia, while demonstrating abnormal re- hol and decreases alcohol intake in alcoholics and their rela- sponses to a benzodiazepine antagonist flumazenil (123, tives (109). A diminished response to brain depressants might occur with a common mutation of the GABAA 6 receptor, The Potential Importance of Dopamine (DA) which might also reflect a low LR to alcohol (32,122). In addition, a possible predisposition toward alcohol depen- This neurotransmitter has broad effects in the brain, includ- dence might link to an area of chromosome 4 near genes ing in the mesolimbic system where it functions as a media- noted to have an impact on GABA functioning (32,125). DA impacts on the risk for Monoamines, including 5-HT, NE, and DA, are metab- heavy drinking and alcoholism through potentially diverse olized in part by MAO. Alcoholics, especially those with mechanisms including the reinforcing effects of the drug, concomitant ASPD, might demonstrate low MAO activi- personality characteristics, and via several psychiatric disor- ties, perhaps reflecting alternate forms of genes, although ders. Ethanol causes the release of DA in the mesolimbic sys- Finally, alcoholics, especially those with multiple alco- tem, affects DA neurons in the ventral tegmentum, and the holic relatives, might have a blunted hormonal response to reinforcement from alcohol decreases when DA antagonists drugs that have impact on NE, especially during withdrawal are given (6,111,112). There might be a general decrease and early abstinence (127). Thus, NE might also increase in overall DA functioning among more violent alcoholics, the alcoholism risk through vulnerability for panic and other as evidenced by lower levels of DA metabolites in the CSF, anxiety disorders. As discussed in Chapter 99, Asian men and women who lack the low km, mitochondrial AN ATTEMPT TO SYNTHESIZE THESE DATA ALDH (i. Heterozygotes enced characteristics that may be relevant to the alcoholism with the ALDH2-1, 2-2 genotype produce higher acetalde- risk. However, it is unlikely that there are 30or so indepen- hyde levels than Asians with ALDH2-1, 2-1, and have an dent genetically influenced trait markers for alcoholism, and enhanced level of response to alcohol and lower risk for thus the findings are likely to represent a more limited num- alcoholism.
Hypothyroidism or hyperthyroidism were reported in 5 studies that included 668 patients with amiodarone cheap 50 mg caverta with mastercard erectile dysfunction drugs bangladesh, 138 patients with propafenone buy caverta 100 mg free shipping erectile dysfunction 21 years old, 136 with sotalol 100mg caverta amex erectile dysfunction protocol diet, 249 with dronedarone buy cheap caverta 50 mg impotence young male, and 202 with either sotalol or 224,230,259-261 propafenone. Hypothyroidism was reported in 29 patients with amiodarone and 2 patients with dronedarone. Hyperthyroidism was reported in 20 patients with amiodarone. Results in Specific Subgroups of Interest Six studies report outcomes by treatment arm for subgroups of patients based on characteristics such as age, sex, type of AF, duration of AF, left atrial size, and presence of heart 180,230,258-261 disease. With few exceptions, the results of primary outcomes did not change by 180,230,260,261 subgroup. In one of these, the probability of remaining in sinus rhythm continued to be significantly greater among patients without ischemic heart disease on amiodarone compared with sotalol (p<0. In the other three subgroup analyses comparing amiodarone with sotalol, there was no such difference between patients with and without a history of heart 230,260,261 disease. In one of three studies comparing amiodarone with sotalol and reporting subgroup analyses by age, there was a higher rate of recurrence of AF or adverse effects from the medication among those patients taking sotalol who were >65 years of age compared with those 260 who were ≤65 years of age (p=0. Finally, in the study comparing the effect of amiodarone with propafenone on the outcome of the recurrence of AF alone, there was a statistically significant lower rate of recurrence among women on amiodarone compared with women on 259 propafenone, but this difference was not seen among males. Strength of Evidence Our review identified 83 studies that evaluated the comparative safety and effectiveness of rhythm-control procedures and drugs for maintenance of sinus rhythm. These studies demonstrated that among patients with AF, there is high strength of evidence that rhythm control using transcatheter PVI is superior to rhythm control using antiarrhythmic medications in reducing recurrent AF over 12 months of followup in patients with paroxysmal AF. This evidence is strongest in younger patients with little to no structural heart disease, and with no or mild enlargement of the left atrium. The evidence also suggested that the duration of AF is an important predictor of response to PVI. Our review also examined whether complex fractionated atrial electrogram (CFAE) ablation in addition to PVI increases the odds of maintaining sinus rhythm during followup compared with PVI only. Based on data from 9 RCTs, we found that CFAE ablation in addition to PVI did not demonstrate a statistically significant increase in maintenance of sinus rhythm compared with PVI only. By combining data from nine RCTs, our review is the largest to date to address this question. Unlike prior reviews, our review showed a potential benefit, but this finding did not 90 reach statistical significance, and we therefore concluded that CFAE ablation in addition to PVI did not increase maintenance of sinus rhythm compared with PVI alone. This difference is 216,223 largely driven by the inclusion of two recent studies not included in prior reviews which did not demonstrate a benefit of CFAE. This finding could inform clinical decision making regarding the extent of ablation during a PVI procedure, especially given the potential for reduced atrial mechanical function from more scarring with CFAE. The low strength of evidence rating for this comparison and outcome underscores the importance of conducting well-powered and designed RCTs to address this issue definitively. Our review also evaluated surgical Maze and determined that there is moderate evidence that rhythm control using surgical Maze at the time of other cardiac surgery (specifically, mitral valve surgery) is superior to mitral valve surgery alone in reducing AF recurrence. We also found that there is strong evidence that rhythm control using PVI at the time of cardiac surgery is superior to cardiac surgery alone or in combination with antiarrhythmic drugs (AADs) or with catheter ablation in reducing AF recurrence over 12 months of followup in patients with persistent AF. Our findings support exploring these interventions further with regard to their effect on final outcomes and in different patient populations. Despite the wide range of antiarrhythmic drugs available in the United States, our review identified only 18 comparative studies eligible for inclusion. Amiodarone, sotalol, and propafenone were the most commonly used antiarrhythmic drugs in RCTs assessing the pharmacological maintenance of sinus rhythm. Only one study (a substudy of the AFFIRM study) systematically assessed differences in all-cause mortality between antiarrhythmic drugs and found no statistically significant difference between amiodarone and sotalol. With regard to maintaining sinus rhythm or decreasing recurrences of AF, amiodarone did not appear to be different from propafenone in the two studies of fair quality that reported results on this comparison. Comparisons of other antiarrhythmic drugs were infrequent and often led to conflicting results. The superiority of one antiarrhythmic medication over another has been debated for years and there has been a long-standing need to review and synthesize the evidence surrounding the comparative effectiveness of different antiarrhythmic medications at maintaining sinus rhythm. However, due to the number of studies, small number of patients enrolled in the studies, and heterogeneity across studies in terms of both patient populations and treatments, the results are inconclusive. Overall, across the included studies additional evidence is needed to explore the impact of available interventions on final clinical outcomes (e. Finally, the evidence base is limited in terms of the exploration of subgroups of interest. Tables 20 and 21 summarize the strength of evidence for the outcomes of interest comparing rhythm-control procedures and drugs for maintenance of sinus rhythm. For those comparisons where the number of studies was sufficient to estimate a summary effect, we were able to have greater confidence in our findings. Strength of evidence domains for rhythm-control procedures Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Transcatheter PVI vs. AADs Maintenance of 8 (921) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 6. PVI AF 1 (67) RCT/ NA Direct Imprecise SOE=Insufficient Hospitalizations Moderate Quality of Life 6 (647) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient Mixed Embolic 2 (140) RCT/Low Consistent Direct Imprecise SOE=Low Events No embolic events Including in either the PVI or Stroke AAD arm Bleeding 1 (67) RCT/ NA Direct Imprecise SOE=Insufficient Events Moderate Transcatheter PVI Using Different Types of Ablation Catheters Maintenance of 3 (264) RCT/Low Consistent Direct Imprecise SOE=Low Sinus Rhythm No difference between different types of ablation catheters Recurrence of 1 (102) RCT/Low NA Direct Imprecise SOE=Low AF No difference between a multipolar circular ablation catheter and a point-by- point PVI with an irrigated tip ablation catheter (p=0. Transcatheter Segmental PVI Restoration of 1 (80) RCT/ NA Direct Imprecise SOE=Insufficient Sinus Rhythm Moderate 92 Table 20. Strength of evidence domains for rhythm-control procedures (continued) Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Maintenance of 5 (500) RCT/Low Inconsistent Direct Imprecise SOE=Low Sinus Rhythm OR 1. Transcatheter PVI Without CTI ablation Recurrence of 2 (257) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient AF Transcatheter PVI With CFAE Ablation vs. Transcatheter PVI Without CFAE Ablation Restoration of 2 (247) RCT/Low Consistent Direct Imprecise SOE=Low Sinus Rhythm 2 studies showing significant benefit of CFAE arm Maintenance of 9 (817) RCT/Low Inconsistent Direct Imprecise SOE=Low Sinus Rhythm OR 1. Transcatheter PVI With Additional Ablation Sites Other Than CTI and CFAE and Transcatheter PVI Involving all Four PVs vs. Transcatheter PVI Involving Arrhythmogenic PVs Only Restoration of 2 (384) RCT/Low Consistent Direct Imprecise SOE=Insufficient Sinus Rhythm Maintenance of 15 (1,926) RCT/ Inconsistent Direct Imprecise SOE=Insufficient Sinus Rhythm Moderate Recurrence of 6 (572) RCT/ Inconsistent Direct Imprecise SOE=Insufficient AF Moderate All-Cause 2 (405) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient Mortality Quality of Life 2 (152) RCT/Low Consistent Direct Imprecise SOE=Low No significant difference between arms in 2 studies Stroke 2 (361) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient 93 Table 20. Strength of evidence domains for rhythm-control procedures (continued) Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Transcatheter PVI Alone vs. Transcatheter PVI Plus Postablation AADs Recurrence of 2 (217) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient AF AF 1 (110) RCT/Low NA Direct Imprecise SOE=Low Hospitalizations No difference between arms Surgical Maze vs. Standard of Care (Mitral Valve Surgery) Maintenance of 7 (361) RCT/Low Inconsistent Direct Precise SOE=Moderate Sinus Rhythm OR 5. Cardiac Surgery Alone or in Combination with AADs or Catheter Ablation Restoration of 3 (181) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 12. Strength of evidence domains for rhythm-control procedures (continued) Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) All-Cause 2 (88) RCT/Low Consistent Direct Imprecise SOE=Low Mortaltiy 2 studies showing no difference between groups CV Mortality 1 (97) RCT/ NA Direct Imprecise SOE=Insufficient Moderate Quality of Life 2 (229) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient Stroke 2 (140) RCT/Low Consistent Direct Imprecise SOE=Low 2 studies showing no difference between groups Bleeding 1 (43) RCT/ NA Direct Imprecise SOE=Insufficient Events Moderate Abbreviations: AAD(s)=antiarrhythmic drug(s); AF=atrial fibrillation; CFAE=complex fractionated atrial electrogram; CI=confidence interval; CTI=cavotricuspid isthmus; CV=cardiovascular; NA=not applicable; OR=odds ratio; PV(s)=pulmonary vein(s); PVI=pulmonary vein isolation; RCT=randomized controlled trial; SOE=strength of evidence Table 21. Strength of evidence domains for pharmacological rhythm-control therapies Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Pharmacological Therapy in Which Electrical Cardioversion is a Key Component of the Treatment Maintenance of 1 (168) RCT/Low NA Direct Imprecise SOE=Insufficient Sinus Rhythm Recurrence of 4 (414) RCT/ Inconsistent Direct Imprecise SOE=Insufficient AF Moderate All-Cause 1 (168) RCT/Low NA Direct Imprecise SOE=Insufficient Mortality Quality of Life 1 (144) RCT/Low NA Direct Imprecise SOE=Insufficient Stroke 1 (168) RCT/Low NA Direct Imprecise SOE=Insufficient Comparison of Pharmacological Agents Maintenance of 9 (2,095) RCT/Low Consistent Direct Imprecise SOE=Low Sinus Rhythm Amiodarone appears better than sotalol, but no different from propafenone Recurrence of 10 (3,223) RCT/Low Inconsistent Direct Imprecise SOE=Low AF Amiodarone appears better than dronedarone or sotalol, but no different from propafenone All-Cause 5 (2,076) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient Mortality CV Mortality 4 (1,664) RCT/Low Consistent Direct Imprecise SOE=Low No difference between study arms in arrhythmic deaths 95 Table 21. Strength of evidence domains for pharmacological rhythm-control therapies (continued) Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) AF 1 (403) RCT/Low NA Direct Imprecise SOE=Low Hospitalizations Rate and mean length of stay of AF hospitalization were lower with amiodarone than with sotalol/ propafenone Control of AF 1 (403) RCT/Low NA Direct Imprecise SOE=Low Symptoms No difference between amiodarone versus sotalol or propafenone Quality of Life 2 (1,068) RCT/Low Consistent Direct Imprecise SOE=Low No significant difference in either study Stroke 2 (1,068) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient Abbreviations: AF=atrial fibrillation; CI=confidence interval; CV=cardiovascular; NA=not applicable; RCT=randomized controlled trial; SOE=strength of evidence Key Question 6. Rate- Versus Rhythm-Control Therapies KQ 6: What are the comparative safety and effectiveness of rate-control therapies compared with rhythm-control therapies in patients with atrial fibrillation? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? Key Points • Based on evidence from 3 RCTs (2 good, 1 fair quality) involving 439 patients, pharmacological rate-control strategies with antiarrhythmic medications are superior to rhythm-control strategies in reducing cardiovascular hospitalizations (high strength of evidence). This 96 finding is based on evidence from 4 RCTs (2 good, 2 fair quality) involving 1,700 patients (low strength of evidence). Description of Included Studies A total of 14 RCTs were included in our analysis (Appendix Table F-6), 12 that explored a 155,156,159,295- rhythm-control strategy using pharmacological therapy versus a rate-control strategy, 303 and 2 that compared a rhythm-control strategy with PVI versus a rate-control strategy that 304 involved AVN ablation and implantation of a pacemaker in one case and rate-controlling 305 medications in the other (poor-quality) study.