CATIE and CUtLASS: can we handle the truth?

Two large, non-commercial clinical trials comparing first- and second-generation antipsychotic drugs for people with chronicschizophrenia in the US and UK have shown unexpected results.In general, the newer drugs were no more effective or bettertolerated than the older drugs. Clozapine outperformed othersecond-generation drugs. The implications are considered.

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INTRODUCTION

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INTRODUCTION

When clozapine was licensed as an antipsychotic in the US andUK over 15 years ago, it seemed a revolutionary drug with improvedefficacy over existing agents.¹ This triggered the developmentof a series of new drugs termed ‘atypical’ (orsecond-generation) on the basis of an apparently reduced riskof neurological side-effects. They were designed to mimic clozapine’spharmacology of lower dopamine D₂ receptor affinity and higheraffinity for other neuroreceptors, in particular 5-HT_2A. Thisnew class of drugs was heralded as the first major advancein the therapeutics of schizophrenia for 40 years. The second-generationdrugs appeared to have important advantages over their first-generation(typical or conventional) predecessors, including better efficacyfor positive, negative and mood symptoms, and improved tolerability. In addition, it was reported that they had cognitive-enhancing effects.² It was also claimed that the higher cost of thesedrugs would be offset by savings resulting from decreased useof healthcare services. None the less, the global antipsychoticdrug market has increased 30-fold since the late 1980s to more than US$15 billion per year.

Despite these claims, meta-analyses and systematic reviews haveprovided only limited support for the superiority of second-generation antipsychotics.^3–5 Much of the evidence about theirefficacy relative to first-generation drugs comes from short-term,industry-funded trials where patients are highly selected,drop-out rates are high and outcomes are based mainly on statistical comparisons of symptom ratings.⁶ As a result, healthcarepolicy makers on both sides of the Atlantic faced a dilemma with respect to the rising costs of mental healthcare and thelack of demonstrably improved outcomes of patients. In addition,many questions remained unanswered. Were the second-generationantipsychotics incontrovertibly superior to the first-generationdrugs and where was the evidence showing that they representeda major advance in routine mental healthcare settings? Weresome better than others? Was clozapine superior to other second-generationantipsychotics? To address these questions, the National Instituteof Mental Health in the US and the NHS Health Technology AssessmentR&D Office in the UK each separately funded a ‘pragmatic’,or practical, clinical trial in the late 1990s, with no sponsorshipfrom industry. Pragmatic trials characteristically have broad inclusion criteria and long follow-up, aiming to mimic routineclinical practice as far as is consistent with a rigorous randomised design.⁷ Their purpose is to clarify the effects of an interventionin real-life clinical practice and patient populations.

Two trials

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Two trials

The US Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)⁸ was a double-blind trial in which 1493 patients withchronic schizophrenia were randomised to one of the second-generationantipsychotics olanzapine, quetiapine, risperidone, ziprasidone(the last was added into the design after the study had begun),or the medium-potency first-generation drug perphenazine. Theprimary aim of the trial was to compare the effectiveness of perphenazine with several second-generation antipsychotics.The primary outcome for the trial, chosen to reflect real-worldpractice, was discontinuation of the drug and switching toanother antipsychotic for any reason, be it lack of efficacy,too many side-effects or patient choice. This outcome was chosen,rather than symptom improvement, since it was felt to encapsulateall kinds of ‘drug failure’ in a simple categorical variable. The trial was run over 57 sites between 2001 and2004 and the sample size had 76% power to detect 12% differencesin discontinuation rates. The participants were in generallargely stable outpatients with a mean illness duration andtreatment history of 14 years. Clinicians prescribed medication to participants under double-blind conditions, with dose titratedagainst clinical response, and analyses later showed that drugdosage used was generally similar to US clinical practice withsome variation.

The results showed, first, that all drugs had limitations, inthat 74% of patients were discontinued from their randomisedtreatment over 18 months. Median time to discontinuation overallwas 4.6 months. Olanzapine proved to be the most effectivein terms of having the lowest discontinuation rate (64%), buthad the highest side-effect burden overall. Surprisingly, theremaining second-generation drugs differed neither from eachother, nor from the first-generation antipsychotic perphenazine,in terms of effectiveness or extrapyramidal side-effects. Therewas no evidence that second-generation drugs were better fornegative symptoms or cognitive deficits.⁹ Individual drugsdiffered in specific side-effects. Olanzapine caused most weightgain and dyslipidaemia, quetiapine caused most anticholinergiceffects, risperidone the most hyperprolactinaemia and sexualside-effects. Perphenazine had highest rates of discontinuationfor extrapyramidal side-effects, even though direct measuresof these effects did not differ significantly between drugs.

CATIE included a subsequent trial for those participants whodiscontinued the first phase because of a lack of efficacy.¹⁰They were invited to be re-randomised to a comparison of open-labelclozapine v. other second-generation antipsychotics, with timeto all-cause discontinuation again as the primary outcome.In the 99 participants entering CATIE phase 2, clozapine emergedas being significantly more effective than the other second-generationdrugs, with a median time to discontinuation of 10 months,twice the length of the next best, olanzapine.

The UK Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS)^11,12 comprised a pair of smaller, open (i.e.not-masked to patients and clinicians) randomised trials comparingclasses of drug as grouped in most clinical guidelines: first-generationv. second-generation drug other than clozapine (CUtLASS 1),and other second-generation drug v. clozapine. Primary outcomewas quality of life at 1 year and symptoms were the main secondaryoutcome. Outcomes were assessed by assessors masked to treatment allocation. In CUtLASS 1, 227 people with schizophrenia, mostlyout-patients, who were being assessed by their clinical teamfor medication review because of poor response or adverse effectswere randomised to either a first-generation or a second-generationdrug other than clozapine (amisulpride, olanzapine, quetiapineor risperidone). The choice of individual drug within eachclass was made by the managing clinician in advance of randomisation.The rate of follow-up interview was 81% at 1 year. The results showed no advantage of second-generation drugs in terms ofquality of life or symptoms over 1 year. In fact, those participantsreceiving a first-generation antipsychotic did rather better.In addition, there were no significant differences in ratesof objectively assessed extrapyramidal side-effects. Participantsreported no clear preference for either class of drug. The CUtLASS2 trial was of similar design and compared clozapine with other second-generation drugs in 136 patients who had not respondedwell to two or more previous drugs. Results showed that therewas a significant advantage for clozapine in symptom improvementsover 1 year; moreover, patients significantly preferred it.

How do these two trials compare? The rationale for each trialwas the perceived need for relevant, real-life trial data toinform policy and routine clinical practice. The trials weredesigned wholly separately of each other and conducted in differenthealthcare systems. The investigators in both trials predictedthat second-generation antipsychotics would outperform first-generationdrugs, and that clozapine would be the most effective. Both trials were government funded and both were designed to reflectroutine clinical practice as much as possible, with broad inclusioncriteria intended to enroll representative patients. The participantswere very similar clinically and demographically in the twotrials. The main results were broadly the same in each trialand surprised both groups of investigators. In both trials,the primary hypotheses were not supported and second-generation antipsychotics were not found to be more effective (with theexception of olanzapine in CATIE). Moreover, they did not producemeasurably fewer extrapyramidal side-effects overall. In bothtrials, clozapine was the most effective for treatment-resistantpatients.

Are first-generation as good as second-generation drugs?

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Are first-generation as good...

Why did both trials fail to find the expected clinical advantagefor second-generation antipsychotic drugs? Could each havehad design flaws? Sample size was not a problem in CATIE. CUtLASShad 75% power to find an effect and the results showed a trendfor participants receiving first-generation drugs to do better,suggesting that a larger sample would not have changed theresult. Another possible problem might be that both trials includedmostly patients with long histories of treatment. This may have limited the scope for any medication to demonstrate improvements.None the less, both trials went on to show that clozapine hada significant advantage. A related issue is that, if patientswere already taking a second-generation drug at baseline andthis presumably was not fully effective, then this meant thatthe sample was biased to non-responders to second-generation antipsychotics. However, in CUtLASS 1 80% of patients werebeing treated with a first-generation drug when referred intothe trial. Moreover, CATIE patients switched at study entryfrom a second-generation antipsychotic to perphenazine didno better (or worse) than those switched to another second-generation drug.^8,13

One possible contributor to the unexpected findings is in choiceof first-generation comparator. In CUtLASS, clinicians chosesulpiride in 49% of cases and in contrast to most industry-sponsoredtrials, haloperidol was chosen in just 8%. Sulpiride has beenviewed anecdotally as having some atypical properties, buta recent Cochrane review¹⁴ finds no evidence to support this.The avoidance by clinicians of high-potency first-generationdrugs and the use of moderate doses in both trials probably explains the failure to find excess rates of extrapyramidaleffects. A further factor in explaining the results was theway the data were analysed, using more advanced methods thanhas been usual in the past. For example, in dealing with theproblem of missing data, both trials chose to avoid the usual practice of using ‘last observation carried forward’for patients who drop out during the trial, where the lastavailable ratings are counted as if they are real end-pointdata. There is now evidence that this produces bias in thefinal results.

There are caveats. One is that neither trial was powered tolook at the issue of tardive dyskinesia, the bête noirof first-generation antipsychotics. Although there is emergingevidence that second-generation drugs may not be as free ofrisk for tardive dyskinesia as once thought, this is stilla potential limitation of first-generation antipsychotics.¹⁵ This needs to be set against the risk of serious metabolicconsequences of some second-generation drugs.

Into the future

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Into the future

In the end, we think that the convergence in the results ofthese two trials is compelling. The finding of clinical equivalencebetween second- and first-generation antipsychotics derivesfurther support from a third trial with a similar pragmatic design,¹⁶ which found no advantage for olanzapine in comparisonwith haloperidol given in lower doses than has been traditional.One issue is the differences in design between the CATIE/CUtLASStrials and most previous trials. CATIE and CUtLASS aspiredto go beyond efficacy comparisons (can drug A work better thandrug B under ideal conditions?) and compare the effectivenessof drug treatments (does drug A work better than drug B asreally used in clinical practice?). We would argue that suchpractical trials are more relevant to policy makers, mentalhealthcare administrators and practitioners, since the resultsthey produce are more generalisable to routine clinical practice.

A final aim of both CATIE and CUtLASS was to look at the economicsof prescribing. In CUtLASS, the detailed costs of direct healthcareover 1 year varied greatly between patients, with a mean of£18 800 for those in the first-generation arm and £20100 in the second-generation arm. Of these costs, just 2.1%and 3.8% were costs of the drugs themselves. For clozapine it was a similarly low proportion, at 4%. Schizophrenia is anexpensive disorder to manage but not because of the pricesof drug treatments. The cost-effectiveness data from the CATIEtrial indicated that perphenazine was significantly less costlyand not less effective than the second-generation antipsychoticsas a group,¹⁷ a result replicated for the first-generationantipsychotics in CUtLASS.¹⁸

Where does this leave prescribers? Our conclusion must be that first-generation drugs, if carefully prescribed, are as goodas most second-generation drugs in many if not most patientswith established schizophrenia. This is good news as it increasesthe range of choices of antipsychotic drugs. Careful prescribingof first-generation antipsychotics means using lower dosesthan was often done in the past and avoiding high-potency drugs.Clozapine clearly remains an important drug where others havefailed. Choosing which drug to switch to may depend on the reasonsfor switching in the first place: lack of efficacy might suggesta switch to olanzapine or clozapine, whereas lack of tolerabilitymight suggest another choice. Note that the findings may notbe the same for first-line treatments^19,20 and that the roleof long-acting medications has yet to be made clear.

It is worth reflecting on how crudely we often use antipsychoticdrugs. Polypharmacy, the prescribing of two or more antipsychoticsin parallel, is widespread despite the lack of evidence tosupport it and the knowledge that it doubles costs and multipliessafety risks. Off-label prescribing is common. It is perhapsnot surprising that, in the context of a severe, chronic illness,clinicians are tempted to resort to untested measures. It isthe same sense of frustration that allowed us to be ‘beguiled’,as Peter Jones described it (Washington Post article 3 October2006, http://www.washingtonpost.com/wp-dyn/content/article/2006/10/02/AR2006100201378.html), by the promise of a new class of drugs. These trials emphasiseagain the urgent need for discovering new, safe, effectivemedications, as well as knowing how to best use our existingtreatments.

REFERENCES

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