Drug-induced Risk of Cardiac Death: NYS Advisory_APA Guidance

The legitimacy of psychiatry’s clinical practices is unraveling as a copious body of evidence—documented in state / federal Medicaid records; in studies that compare the effects of drugs to placebo; in retrospective analyses of medical records, death reports, and internal company documents uncovered during product liability litigation—reveals that the drugs psychiatrists prescribe are harming rather than helping patients. After decades of denial, psychiatry is confronted with mounting evidence demonstrating that the so-called new ‘atypical’ antipsychotic drugs are seriously undermining patients’ physical and mental health and shortening lives. These drugs are at the subject of heated debate, government investigation, and mass litigation.

A 2007 meta-analysis found: “In recent decades, the differential mortality gap associated with schizophrenia has been increasing…compared with the general population, people with schizophrenia have a 2- to 3-fold increased risk of dying…the potential [exists] for an even greater disease burden as a result of the introduction of second-generation antipsychotic medications.” [1] http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123 

 Indeed, numerous studies have shown that these drugs are toxic to the heart: they induce arrhythmias and the metabolic syndrome which increases the risk of death from coronary heart disease, as well as diabetes, hyperglycemia, and stroke. [2] [3]             

 A report in The New England Journal of Medicine (2009) [4]          http://content.nejm.org/cgi/content/short/360/3/225  finally prompted the New York State Office of Mental Health (NYS OMH) to issue an advisory to psychiatrists (Feb 16, 2009) on the use of antipsychotic medications for adult patients. For the first time, OMH acknowledges:

 "There is mounting evidence, now reported in a variety of journals and the popular press, that:

•     there are neither clear nor consistent distinctions in the clinical effectiveness between first and second generation APs (with clozapine the exception)

•     there are cardiometabolic risks associated with specific first and second generation antipsychotics

•     there are risks for neurologic extrapyramidal side effects with specific APs, particularly the higher potency first generation APs

•    there is a small risk of sudden cardiac death associated with APs

 The NEJM report by a Vanderbilt University team of physicians, pharmacologists, and epidemiologists—including a rheumatologist and cardiologist—is a comprehensive study that analyzed the Tennessee Medicaid data (Jan 1, 1990 to Dec. 31, 2005) for adults aged 30 to 74. They confined the analysis to current users of antipsychotic drugs, 93,300  (44,218 were prescribed a typical (older) antipsychotic and 46,089 were prescribed an ‘atypical’ antipsychotic. Nonusers of antipsychotic drugs numbered 186,600.

Typical antipsychotics prescribed: Haldol (haloperidol) and Thorazine (thioridazine). Atypical antipsychotics prescribed: Clozaril (clozapine), Zyprexa (olanzapine), Seroquel (quetiapine) and Risperdal (risperidone).

 The researchers matched users and nonusers (according to the predicted probability that a person would be a user of antipsychotic drugs) and compared the incidence of sudden cardiac death. The findings are clear and unequivocal:

“Current users of typical and of atypical antipsychotic drugs had higher rates of sudden cardiac death than did nonusers of antipsychotic drugs.” http://content.nejm.org/cgi/content/short/360/3/225 

 An editorial in the same issue of the NEJM (excerpt below) [5] by two prominent Harvard expert pharmacoepidemiologists, Sebastian Schneeweiss, M.D., Sc.D., and Jerry Avorn, M.D., commends the Vanderbilt team for their especially "well designed" "comprehensive" study which "accurately represents events that happen shortly after initiation of therapy."

 Persuaded by the evidence demonstrating the significant risk for cardiac death from antipsychotics, Drs. Schneeweiss and Avorn advocate sharp reductions in the use of antipsychotics for off-label indications—in particular for children and the elderly.

“In the absence of clearly established benefits…the risk of a fatal side effect is not likely to be acceptable.” 

 They recommend establishing a risk-management program to protect patients, noting such a program has been in place for two decades to monitor for reduction in white blood cells in patients taking clozapine. The rate of death due to clozapine-induced agranulocytosis was 0.2 per 1,000 patient years. Whereas the risk of sudden cardiac death from antipsychotics, they note, was substantially higher: 2.9 deaths per 1,000 patient years at low dose, and 3.3 deaths per 1,000 at high dose. 

Their reasonable recommendation:

“if an antipsychotic agent is necessary, it seems reasonable to obtain an electrocardiogram before and shortly after initiation of treatment with an antipsychotic drug. This modest effort could enable each patient starting on a high-dose antipsychotic to be screened for existing or emergent prolongation of the QT interval.”                                 http://content.nejm.org/cgi/content/full/360/3/294

The OMH advisory is accompanied by a Guidance document issued by the American Psychiatric Association (APA) authored by Dr. Jeffrey Lieberman, Chairman of Psychiatry, Columbia University and Director of the NYS Psychiatric Institute.  The APA Guidance demonstrates psychiatry’s fierce resistance to evidence-based medicine.     http://www.omh.state.ny.us/omhweb/advisoriesadult_antipsychotic_use_attachement.html

Dr. Lieberman questions the validity of the Vanderbilt study using obtuse arguments and a tortured line of reasoning that is all but unintelligible. 

He acknowledges that the old antipsychotics are associated with sudden cardiac death, but denies the evidence showing that the much more widely prescribed, atypical antipsychotics pose at least double the risk of death. The following statement encapsulates psychiatry’s disregard for evidence: 

“the finding that second-generation agents were associated with a comparable risk was new information and surprising as the newer medications have been considered to be generally safer.”

The evidence, however, shows that the risk of cardiac death is slightly higher for patients prescribed an atypical: The incidence-ratio “among users of typical antipsychotic drugs increased from 1.31 (range: 0.97 to 1.77) for those taking low doses to 2.42 (1.91 to 3.06) for those taking high doses (P<0.001). Among users of atypical agents, the incidence-rate ratios increased from 1.59 (1 .03 to 2.46) for those taking low doses to 2.86 (2.25 to 3.65) for those taking high doses (P=0.01).

Dr. Lieberman was a leading investigator in the government sponsored, schizophrenia effectiveness study, CATIE (2005) [6] which found no difference in effectiveness between the old and new antipsychotics, but documented profound harm produced by the atypicals. Dr. Lieberman, et al reported that: 64% to 70% of patients in the CATIE study (number of patients, 1,460, mean age, 40) suffered “moderate to severe” adverse events; 74% dropped out; and 3% of patients who were treated with Risperdal and Seroquel had prolongation of the QT interval. [5, see, Table 3] 

Drs. Schneeweiss and Avorn note:

“It is striking that it took so long to establish the elevated risk associated with atypical antipsychotic medications given that the first agent in this class (clozapine) entered the U.S. market in 1989.”

The answer is psychiatry has not been guided by the “do no harm” principle of medicine, nor has it adhered to scientific standards of objectivity. For two decades, psychiatry’s leadership enthusiastically promoted these drugs in journal articles, at professional conferences, and continuing medical education courses as “safer and more effective” than the old neuroleptics. Prominent academic psychiatrists persuaded colleagues that the drugs were safe to use for untested, unapproved, off-label conditions and for vulnerable children and the elderly. Their careers and substantial source of extra income are invested in promoting the delusion that the drugs are "safe and effective."

The OMH advisory does not recommend a reduction in the use of these drugs, declaring: “Antipsychotic medications remain a mainstay in the effective treatment of psychotic illnesses…” And Dr. Lieberman, writing on behalf of the APA, rejects the safeguards recommended by Drs. Schneeweiss and Avorn: “Instituting a policy of routine serial measurement of the QTc interval in all patients initiating treatment with antipsychotic medication may be premature.” http://www.omh.state.ny.us/omhweb/advisories/adult_ antipsychotic_use_attachement.html

Sudden cardiac death is not the only dose-related, potentially lethal cardiovascular risk linked to the atypicals.  The drugs interfere with normal metabolic function inducing a cascade of life-threatening risks which increase mortality among users.

A meta-analysis of 37 studies in the Archives of General Psychiatry (2007) [1] documented a widening gap in the standardized mortality rate between patients with schizophrenia and the general population.  The authors suggest that the mortality rate they calculated “captures only a fraction of the eventual burden of mortality associated with the adverse effect profile of the second generation antipsychotic medications.”

They found:

“compared with typical antipsychotics, several of the second-generation antipsychotics are more likely to cause weight gain and metabolic syndrome. Because the metabolic syndrome is associated with a 2-to 3-fold increase in cardiovascular mortality and a 2-fold increase in all-cause mortality, these adverse effects would be expected to contribute to even higher mortality rates in the next few decades.” 

Furthermore,

“Adverse health outcomes associated with weight gain and/or metabolic syndrome (eg, myocardial infarction, cerebrovascular accidents, or cancer) may take decades to fully emerge.”  http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123

 

 In light of the multiple, cumulative debilitating and fatal risks posed by antipsychotics, and "the absence of clearly established benefits," these drugs are unacceptable for use–except in crisis situations for short duration.

 But psychiatry’s practices are governed by neither humanitarian medicine, nor evidence-based medicine. The profession denies the scientific evidence and the drug-induced deteriorating condition of their patients–some of who gain more than 125 lbs develop diabetes and cardiovascular illnesses.  Psychiatrists cling to a self-perpetuating delusion, the belief that the drugs they prescribe are “well tolerated, safe and effective” when the evidence clearly shows them not to be either. Psychiatry has a professional and financial investment in promoting the belief that its treatments are successful:

“The reputed success of psychiatric drug treatments has been foundational to the efforts of psychiatrists to elevate their field’s status within the medical community.” [7]

 Pity the patients who are condemned to the ministrations of uncaring and unyielding professionals who cling to a failed, inhumane paradigm of care that undermines patients’  health, increases suffering, and shortens their lives.

 “They shoot horses, don’t they?”

 References:

1.         Sukanta Saha, MSc, MCN; David Chant, PhD; John McGrath, MD, PhD, FRANZCP A Systematic Review of Mortality in Schizophrenia: Is the Differential Mortality Gap Worsening Over Time? Arch Gen Psychiatry. 2007;64(10):1123-1131 http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123

2.         Joukamaa M, et al. Schizophrenia, neuroleptic medication and mortality, British J of Psychiatry, 2006;188:122-127.

3.         See, numerous studies cited by Moncrieff J. in The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment, 2008, Palgrave Macmillan.

4.         Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. NEJM 2009; 360:225-235.

5.         Sebastian Schneeweiss, M.D., Sc.D., and Jerry Avorn, M.D. Antipsychotic Agents and Sudden Cardiac Death —How Should We Manage the Risk?  NEJM 2009, 360:294-6.

6.         Lieberman JA, Stroup S, McEvoy JP, et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia, NEJM 2005; 353:1209-23.

7.         Horowitz A. Book Review, NEJM 2009; 360:841-44.

 

http://www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use.html

OMH Advisory On Antipsychotic Medication Use In Adults Lloyd I. Sederer, MD Medical Director February 16, 2009

Dear Colleague,

This OMH Advisory is on the use of antipsychotic medications (APs) for adult patients served by the New York State Office of Mental Health. We hope these comments will be of value to others in the mental health community.

There is mounting evidence, now reported in a variety of journals and the popular press, that:

*           although there are differences between individual AP drugs there are neither clear nor consistent distinctions in the clinical effectiveness between first and second generation APs (with the exception of clozapine) as classes of drugs

*           there are significant risks of prescribing APs to individuals with dementia – See OMH Advisory. <http://www.omh.state.ny.us/omhweb/advisories/advisory_fda_antipsychotic.htm

*           there are cardiometabolic risks associated with specific first and second generation APs

*           there are risks for neurologic extrapyramidal side effects with specific APs, particularly the higher potency first generation APs

*           there is a small risk of sudden cardiac death associated with APs

All medications carry risks (and have side effects). The work of prescribing clinicians is to identify benefit and risk and help patients make informed decisions about their health and treatment.

Antipsychotic medications remain a mainstay in the effective treatment of psychotic illnesses thereby calling for even greater care regarding which agent we recommend to each individual patient – and what monitoring we provide before and during the course of treatment. Recall, as well, that the risk of relapse is far greater in people with psychotic illness if they do not take APs – as noted in OMH Advisory on APs <http://www.omh.state.ny.us/omhweb/advisories/antipsychotic_medications.html> .

Recent concerns about the risk of sudden cardiac death in people taking APs led the American Psychiatric Association (APA) to issue the attached guidance document <http://www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use_attachement.html> . This release comes from the APA Council on Research, chaired by Dr. Jeffrey Lieberman, the Director of the New York State Psychiatric Institute and Chair of Psychiatry at Columbia.

The OMH Medical Director’s office is working with Dr. Lieberman on a template to provide guidance to each OMH prescribing clinician to review the AP medications of all their patients. We envision a decision tree for existing patients at the time of their next appointment and for all new patients. This is a complex endeavor and one that warrants the careful thought of experts, which we have undertaken. We hope that this work also will be useful to colleagues outside of the OMH.

As you see your patients, please be sure to continue to consider benefit, risk, side effects, drug-drug interactions, the lowest doses possible for effectiveness, and the importance of psychosocial treatments for all patients who meet indications for the prescription of an AP medication (or any medication for that matter).

We welcome your comments.

Please feel free to distribute this material to your colleagues.

Sincerely,

Lloyd I. Sederer, MD

Medical Director, NYS Office of Mental Health

———–

 <http://www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use_attachement.html#ft>

APA Guidance on the Use of Antipsychotic Drugs and Cardiac Sudden Death Prepared by Jeffrey A. Lieberman, M.D., David Merrill, M.D., and Sharat Parameswaran, M.D.  for the APA Council on Research

In the January 15, 2009, issue of the New England Journal of Medicine, Wayne A. Ray, PhD, and colleagues reported findings of a study investigating the risk of sudden cardiac death (SCD) associated with the use of antipsychotic medications (Ray et al., 2009). The researchers used a Tennessee Medicaid database to retrospectively calculate the incidence of SCD among 44,218 users of typical (i.e. first-generation) agents, 46,089 users of atypical (i.e. second-generation) agents and 186,600 nonusers of antipsychotic drugs. The patients included in the study were 30 to 74 years of age, and predominantly women, white and residing in urban areas. The individual drugs that were analyzed were haloperidol, thioridazine, clozapine, olanzapine, quetiapine and risperidone.

Ray and colleagues found that both antipsychotic classes were associated with an approximate doubling of the risk of SCD, relative to the baseline rate among nonusers of antipsychotics. In absolute terms, the incidence of SCD among patients prescribed antipsychotics was approximately three events per 1000 patient-years. This risk was dose-dependent in both medication classes, with doses equivalent to 300 mg or more of chlorpromazine per day posing the greatest risk.

That first-generation antipsychotics are associated with SCD is well established (Ray et al., 2001; Straus et al., 2004), but the finding that second-generation agents were associated with a comparable risk was new information and surprising as the newer medications have been considered to be generally safer.

Careful examination of the study methodology, however, raises questions about the validity of the results. Ray and colleagues used a retrospective analysis of death certificates to evaluate mortality by SCD, which may overestimate SCD incidence. Multiple studies using a prospective, multiple-source surveillance method (Chugh et al., 2004; Byrne et al., 2008; Vaillancourt et al., 2004) have shown rates of SCD in the general population between 51 and 56 per 100,000 person-years, compared to 143 per 100,000 person-years in the study by Ray and colleagues. A direct comparison between the prospective and retrospective methods showed a positive predictive value of only 19% with the latter method (Chugh et al., 2004). In addition, Ray and colleagues utilized an unvalidated cardiovascular risk score to assess patients’ risk for SCD, noting a non-significantly lower baseline risk score in patients receiving antipsychotic medications than in those not receiving them. This finding is inconsistent with existing evidence regarding high rates of cardiovascular morbidity and mortality in patients with mental illness, particularly severe mental illness (Newcomer et al, 2007; Osborn et al., 2006; Goff et al., 2005). Indeed, a lower calculated cardiovascular risk in patients taking antipsychotic medication may actually reflect the well-known low rates of detection and treatment of cardiovascular risk factors in patients with mental illness (Nasrallah et al., 2006), which may account for the higher rate of cardiac-related mortality among antipsychotic users in this study. Neither cardiovascular risk nor primary mental illness was controlled for in the primary cohorts analyzed by Ray and colleagues; a secondary set of cohorts, while better matched for mental illness, specifically excluded patients with schizophrenia. Without controlling for these potentially confounding variables, it is unclear whether the high rates of cardiac mortality reported in this study were attributable to antipsychotic medications or other causes.

 Ray and colleagues suggested that the most likely mechanism of SCD among antipsychotic users is a drug-induced blockade of repolarizing currents in cardiac myocytes, leading to a prolongation of the electrocardiogram (ECG) rate-corrected QT interval (QTc), and ultimately to the potentially fatal ventricular tachyarrhythmia torsades de pointes (TdP). An accompanying editorial (Schneeweiss and Avorn, 2009) proposed that an ECG be obtained before and shortly after initiation of treatment with an antipsychotic drug. According to the editorial, when QT interval prolongation is detected, the antipsychotic dose should be reduced or the drug discontinued, other risk factors for SCD should be addressed, and follow-up ECGs should be obtained.

 Instituting a policy of routine serial measurement of the QTc interval in all patients initiating treatment with antipsychotic medication may be premature. While some antipsychotics are known to substantially prolong the QTc, others do so to only a modest degree (Harrigan et al., 2004). Furthermore, although prolongation of the QTc is the best available clinical surrogate for the development of TdP, it is an imperfect biomarker (Shah, 2005; Sager, 2008). The QTc generally has low specificity for predicting arrhythmias, and for some drugs a dissociation exists between QTc prolongation and TdP risk (Sager, 2008).

 Given the methodological limitations of the study by Ray and colleagues, and the lack of data regarding the utility and cost-effectiveness of serial QTc measurement in antipsychotic-treated patients, clinicians should continue to observe extant practice guidelines for the work-up and management of psychotic patients. With regard to cardiac safety, these include obtaining a medical and medication history, a thorough physical exam, vital signs and routine laboratory tests (APA, 2006). Thioridazine, mesoridazine and pimozide should not be prescribed for patients with cardiac risk factors of known heart disease, a personal history of syncope, a family history of sudden death under age 40, or prolonged QTc syndrome (Marder et al., 2004). If these agents are prescribed, serum potassium and an ECG should be checked before drug initiation; serum potassium and an ECG should also be checked in the presence of the above cardiac risk factors prior to treatment with ziprasidone (APA, 2004). An ECG should be checked again following a significant change in dose of thioridazine, mesoridazine, pimozide or, in the presence of cardiac risk factors, ziprasidone, or following the addition of another QTc-prolonging medication (APA, 2004), or if a patient presents with symptoms associated with a prolonged QTc interval (e.g., syncope) (Marder et al., 2004). An absolute QTc interval of >500 msec or an increase of 60 msec from baseline may be associated with an increased risk of TdP (Haddad and Anderson, 2002) and should prompt reduction or discontinuation of the offending agent.

 When prescribing antipsychotic medication, clinicians are encouraged to use the lowest dose effective for any given patient in order to minimize dose-dependent adverse effect risks.

~~~~~~~~~~~~~~~~~ 

http://content.nejm.org/cgi/content/full/360/3/294

Antipsychotic Agents and Sudden Cardiac Death —How Should We Manage the Risk?Sebastian Schneeweiss, M.D., Sc.D., and Jerry Avorn, M.D. NEJM 2009, 360:294-6.

EXCERPT

 It is striking that it took so long to establish the elevated risk associated with atypical antipsychotic medications given that the first agent in this class (clozapine) entered the U.S. market in 1989. Ray et al. present a comprehensive study that makes a clear case for the increased risk of sudden cardiac death associated with all antipsychotic drugs. Their research has all the attributes of a well-designed pharmacoepidemiologic study; many of these attributes seem obvious but are too often poorly implemented. The authors confine their analysis to new users of the study drugs; this design accurately represents events that happen shortly after the initiation of therapy, events that could otherwise be underestimated by including the greater person-time contributed by long-term users (or “survivors”) of the drug, who may be less susceptible to the outcome that is being studied.7 They also establish a clear temporal sequence between patient characteristics before the initiation of treatment and the outcomes after initiation.

 Sudden cardiac death can be a difficult end point to capture in databases of health care use.

Ray et al. developed and tested an algorithm that combined information from death certificates with data on health care use. This algorithm resulted in a positive predictive value of 86%, which would result in only minor underestimation of risk.

 Should the use of antipsychotic medications be restricted on the basis of these data? Much of their use is in vulnerable populations and outside the labeled indications, including the use in children and in the elderly with dementia,1,2 and there is much less evidence of efficacy in these populations. In the absence of clearly established benefits for many of these patients, the risk of a fatal side effect is not likely to be acceptable. For these patients, the use of antipsychotic medications should be reduced sharply, perhaps by requiring an age-dependent justification for their use…… see: http://content.nejm.org/cgi/content/full/360/3/294