Discontinuation of Antihyperlipidemic Drugs -- Do Rates Reported in Clinical Trials Reflect Rates in Primary Care Settings?

doi:10.1056/NEJM199504273321703

Volume 332:1125-1131		April 27, 1995		Number 17

Discontinuation of Antihyperlipidemic Drugs — Do Rates Reported in Clinical Trials Reflect Rates in Primary Care Settings?

Susan E. Andrade, Sc.D., Alexander M. Walker, M.D., Dr.P.H., Lawrence K. Gottlieb, M.D., M.P.P., Norman K. Hollenberg, M.D., Ph.D., Marcia A. Testa, M.P.H., Ph.D., Gordon M. Saperia, M.D., and Richard Platt, M.D.

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ABSTRACT

Background Discontinuation rates for drugs used to treat chronicconditions may affect the success of therapy. However, the discontinuationrates reported in clinical trials may not reflect those in primarycare settings.

Methods We conducted a cohort study using computerized researchfiles and medical records on 2369 new users of antihyperlipidemictherapy at two health maintenance organizations (HMOs) from1988 through 1990. The rates of drug discontinuation in theseprimary care settings were compared with the rates reportedin clinical trials published from 1975 through 1993, locatedwith the Medline data base.

Results In the HMOs, the one-year probability of drug discontinuationwas 41 percent for bile acid sequestrants (95 percent confidenceinterval, 38 to 44 percent), 46 percent for niacin (95 percentconfidence interval, 42 to 51 percent), 15 percent for lovastatin(95 percent confidence interval, 11 to 19 percent), and 37 percentfor gemfibrozil (95 percent confidence interval, 31 to 43 percent).For the bile acid sequestrants, niacin, and gemfibrozil, therisks of discontinuation were substantially higher in the HMOsthan in randomized clinical trials, in which the summary estimatesof this risk were 31 percent, 4 percent, and 15 percent, respectively,for trials of one year or longer. The rates of discontinuationin open-label studies were similar to those in the HMOs.

Conclusions The discontinuation rates reported in randomizedclinical trials may not reflect the rates actually observedin primary care settings. The effectiveness and tolerabilityof antihyperlipidemic medications should be studied furtherin populations that typically use the agents.

Five large-scale, randomized clinical trials of antihyperlipidemicdrugs¹^,²^,³^,⁴^,⁵ have suggested that most patients continue receivingthe agents for long periods of time. Reported rates of discontinuationor dropping out range from approximately 4 percent¹ to 15 percent²^,³in the first year of antihyperlipidemic treatment and from approximately11 percent¹ to 30 percent²^,⁴^,⁵ with five or more years of follow-up.

In clinical trials, the services made available to patientsto manage drug side effects and improve compliance are usuallymore extensive than those provided in routine clinical practice.Selection criteria intended to provide a clear therapeutic contrastmay produce study groups that tolerate drug therapy better thantypical populations of patients. Four of the aforementionedtrials¹^,²^,⁴^,⁵ enrolled only middle-aged men, and each excludedpatients with diseases or conditions that are common in populationsrequiring antihyperlipidemic therapy. These included coronaryheart disease,²^,⁴^,⁵ diabetes mellitus requiring treatment withinsulin¹^,²^,³^,⁴^,⁵ or oral hypoglycemic agents,³^,⁴^,⁵ hypertension,⁴^,⁵and notable obesity.⁴ Subjects unlikely to have good compliance¹^,⁴were also excluded.

Because lifelong treatment is generally necessary in personswith high lipid levels, the discontinuation of antihyperlipidemicdrugs signals a failure of therapy due to the patient's intoleranceor to therapeutic ineffectiveness. To obtain more representativeestimates of the rate of discontinuation of antihyperlipidemicdrugs in primary care settings, we evaluated the risks of discontinuationin patients enrolled in two health maintenance organizations(HMOs) and compared them with discontinuation rates for thesame drugs reported in long-term clinical trials.

Methods

Cohort Study

A retrospective cohort study (unpublished data) was performedwith the computerized files and full-text medical records ofthe Fallon Community Health Plan (FCHP) and the Harvard CommunityHealth Plan (HCHP), two HMOs operating in central and easternMassachusetts. The study population consisted of all FCHP memberswith a diagnosis of hyperlipidemia (codes 272.00 to 272.90 ofthe International Classification of Diseases, Ninth Revision)from January 1, 1988, through December 31, 1990, and all HCHPmembers with diagnosed lipid disorders (Computer-Stored AmbulatoryRecord code B001, B003, B005, B006, B160, or S122 or laboratoryevidence of a lipid abnormality) from October 1, 1988, throughSeptember 30, 1990, who began antihyperlipidemic therapy withthe bile acid sequestrants cholestyramine and colestipol orwith niacin, lovastatin, gemfibrozil, probucol, dextrothyroxine,or clofibrate and who had prescription-drug coverage throughoutthe study period. For all eligible study subjects, data on sex,date of birth, concomitant drug use, concomitant diagnoses,dosage of any antihyperlipidemic drugs, serum lipid levels (HCHPmembers only), and referral to the Lipid Clinic (FCHP membersonly) were acquired through the computerized data bases of thetwo HMOs.

Potential discontinuation of antihyperlipidemic therapy wasflagged by identifying patients who switched from one antihyperlipidemicagent to another during the study period, patients for whommore than six months elapsed between the last refill of a prescriptionfor an antihyperlipidemic drug and the end of the study periodor the termination of participation in the plan, and patientsfor whom omitted or inactive antihyperlipidemic therapies wereflagged in the clinical-encounter files (HCHP members only).For each patient so identified, additional information on thediscontinuation of antihyperlipidemic therapy and the reasonfor it was obtained by reviewing the medical chart. Drug coursesthat were discontinued by the physician because the patienthad acceptable serum cholesterol levels or that were stoppedtemporarily were not considered to constitute discontinuationsfor the purposes of the primary analyses. For each drug andfor all drug therapies combined, curves were constructed bythe product-limit method⁶ to show the cumulative incidence (orrisk) of drug discontinuation, drug discontinuation due to adverseeffects, and drug discontinuation due to therapeutic ineffectivenessduring a particular period. The rates of discontinuation ofclofibrate, dextrothyroxine, probucol, and specific combinationsof two or more agents are not reported but are included in theoverall estimate.

Reported Long-Term Clinical Trials

We used the Medline data base to locate all primary reportsof clinical trials published in English from January 1975 throughDecember 1993 that examined the efficacy or safety of cholestyramine,colestipol, niacin, lovastatin, or gemfibrozil in treating lipiddisorders or preventing morbidity or mortality from coronaryheart disease in adults. We excluded studies that had lastedless than six months, that had enrolled fewer than 30 patientsin the treatment group of interest, or that included ambiguousinformation on the number of subjects enrolled or dropping out.We used the overall reported dropout rates, which included butwere not limited to discontinuations due to adverse effectsand therapeutic ineffectiveness. We excluded subjects who didnot meet the eligibility criteria for the study⁷^,⁸ and thosewho were given substandard formulations of the agents.⁸ Whenmore than one dosage or formulation was assessed, we chose themean rate of discontinuation. We used the reported rate of discontinuationfor the entire study population, including other treatment groups,when the investigators did not report regimen-specific discontinuationrates but did indicate that there was no significant differencein rates between the groups.⁹^,¹⁰

We also obtained published open-label drug studies that metthe same criteria as the clinical trials. For the purposes ofour analysis, reported deaths were not considered to be discontinuations.Asymptotic 95 percent confidence intervals for the risks ofdiscontinuation were calculated from the reported standard errorsor from the raw counts, where available.

To estimate summary values, we summed the logit of the riskof discontinuation (log[R/(1-R)]) for each study, weighted bythe inverse variance [R(1-R)/SE]², where R is the reported rateof discontinuation and SE the standard error. The variance ofthe weighted sum was taken as the inverse of the sum of theweights. Overall estimates of the rate of discontinuation werethen recalculated from the logit values.

Results

Cohort Study

There were 2369 eligible study subjects, including 1309 FCHPmembers and 1060 HCHP members. The mean age of the FCHP memberswas 58 years, and 55 percent were female. The mean age of theHCHP members was 55 years, and 48 percent were female. In all,these patients were exposed to 3223 courses of therapy. Thecharacteristics of the patients, including concomitant diagnosesand drug use, are shown in Table 1.

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Table 1. Characteristics of the HMO Patients Who Were Receiving Antihyperlipidemic Therapy during the Study Period.

Data on the frequency with which antihyperlipidemic drugs werediscontinued in the HMOs are presented in Table 2 accordingto the type of drug and the reason for discontinuation. Of the3223 courses of antihyperlipidemic treatment, a total of 1047courses (32 percent) were discontinued. An additional 38 coursesof treatment (1 percent) were stopped temporarily because ofhospitalizations or transient side effects.

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Table 2. Courses of Antihyperlipidemic Therapy Discontinued during the Study Period in the Patients from the Two HMOs, According to the Reasons for Discontinuation.

Among the 1047 discontinued courses of therapy, 582 (56 percent)were followed by a switch to a new therapy, 120 (11 percent)by treatment with agents in addition to the one originally prescribed,27 (3 percent) by treatment with one agent of a combinationoriginally prescribed, and 318 (30 percent) by no further drugtherapy during the study period. The median time from the startof observation to the discontinuation of therapy or the completionof the observation period was 190 days (range, 1 to 1093).

The principal reasons for the discontinuation of drug therapywere adverse effects (in 18 percent of all courses given), therapeuticineffectiveness (in 10 percent), and noncompliance (in 2 percent).Other reasons, from the perspective of the patient, includeda lack of desire to continue receiving the medication (oftendue to a preference for nonpharmacologic methods of loweringcholesterol levels or anxiety about potential side effects ofthe drug), hospitalization, and concomitant serious illness.In 78 cases, more than one reason was listed for discontinuingthe drug.

Adverse effects were noted as a contributing factor in 587 ofthe 1047 discontinued courses of drugs (56 percent), and therapeuticineffectiveness was noted in 324 such courses (31 percent).These contributing causes were present in similar proportionsat the two study sites.

The frequency of drug discontinuation due to adverse effectsranged from 7 percent in patients receiving lovastatin to 26percent in patients receiving niacin. The frequency of discontinuationdue to therapeutic ineffectiveness ranged from 2 percent withlovastatin to 15 percent with gemfibrozil. For both adverseeffects and therapeutic ineffectiveness, the proportional numberof discontinuations differed significantly (P<0.001) accordingto the agent received. Among discontinuations with known causes,the relative contribution of adverse effects as a documentedcause was 67 percent with the bile acid sequestrants (280 of420), 63 percent with niacin (192 of 304), 65 percent with lovastatin(35 of 54), and 40 percent with gemfibrozil (46 of 115). Therelative contribution of therapeutic ineffectiveness as a documentedcause of drug discontinuation was 28 percent with the bile acidsequestrants (116 of 420), 34 percent with niacin (102 of 304),24 percent with lovastatin (13 of 54), and 58 percent with gemfibrozil(67 of 115). The overall differences between types of drugswere apparent at both study sites.

The cumulative incidence of discontinuation associated witheach antihyperlipidemic drug at the HMOs is shown in Figure 1,both overall and according to cause. For all treatments combined,the cumulative incidence of discontinuation after one year was38 percent. The estimated one-year risk of discontinuation wassimilar for all the drugs except lovastatin: it was 41 percentfor the bile acid sequestrants (95 percent confidence interval,38 to 44 percent), 46 percent for niacin (95 percent confidenceinterval, 42 to 51 percent), 15 percent for lovastatin (95 percentconfidence interval, 11 to 19 percent), and 37 percent for gemfibrozil(95 percent confidence interval, 31 to 43 percent). The cause-specificrisks of discontinuation for the various drugs were proportionateto the overall risks, with adverse effects as the predominantcause except in the case of gemfibrozil, for which the principalreason for discontinuation was therapeutic failure.

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Figure 1. Cumulative Incidence of Drug Discontinuation in the Patients from the Two HMOs, According to Causeof Discontinuation.
The thick lines indicate the overall risk of drug discontinuation, the broken lines the risk of discontinuation due to adverse effects, and the thin lines the risk of discontinuation due to therapeutic ineffectiveness.

Rates of Drug Discontinuation in Long-Term Clinical Trials

We examined 30 long-term clinical trials¹^,²^,³^,⁴^,⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹that evaluated the safety or efficacy of antihyperlipidemicagents. These trials ranged in length from six months to sevenyears; there were 17 randomized trials¹^,²^,³^,⁴^,⁷^,⁹^,¹⁰^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁷^,¹⁸^,²⁶^,²⁷^,²⁸^,³⁰and 13 open-label studies.⁸^,¹¹^,¹⁴^,¹⁶^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁹^,³¹Table 3 and Table 4 list the principal findings of the randomizedclinical trials and open-label trials, respectively, and showestimates of the frequency of discontinuation of antihyperlipidemictherapy as compared with our findings in the two HMOs.

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Table 3. Long-Term Randomized Clinical Trials of Antihyperlipidemic Agents.

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Table 4. Long-Term Open-Label Trials of Antihyperlipidemic Agents.

Figure 2 shows the risk estimates for the discontinuation ofantihyperlipidemic drugs reported in randomized clinical trialsof one year or more as compared with the risks in the HMOs afterone year and (where appropriate) two years. The reported estimatesof the discontinuation rates in the six trials of bile acidsequestrants⁴^,⁹^,¹³^,¹⁴^,²⁷^,³⁰ and one of the lovastatin trials¹²were calculated for periods in excess of 1 year (range, 36 monthsto 7 years). The life-table estimates of the failure rate forthe bile acid sequestrants, niacin, and gemfibrozil all differedsignificantly between the HMOs. However, the differences betweenthe two HMOs in estimated one-year discontinuation rates wererelatively minor and were less substantial than the discrepanciesin rates between the HMOs and the published clinical trials.

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Figure 2. Risks of Drug Discontinuation over Periods of One Year or More as Reported in Randomized Clinical Trials and in the Two HMOs Studied.
HMO 1 and HMO 2 refer to the two HMOs studied. Bars represent 95 percent confidence intervals.

Each agent studied except lovastatin was discontinued at higherrates in the HMOs than in randomized clinical trials over similarperiods. The summary estimates of discontinuation rates forrandomized trials of one year or more were as follows: 31 percent(95 percent confidence interval, 30 to 33 percent) for the bileacid sequestrants, 4 percent (95 percent confidence interval,3 to 5 percent) for niacin, 16 percent (95 percent confidenceinterval, 15 to 17 percent) for lovastatin, and 15 percent (95percent confidence interval, 13 to 16 percent) for gemfibrozil.The estimated rates in the open-label studies were similar tothe rates observed in the HMOs.

Discussion

The risk of discontinuing antihyperlipidemic drugs in the twoHMOs one year after the start of therapy ranged from 15 percentfor lovastatin to 46 percent for niacin. For the bile acid sequestrants,gemfibrozil, and niacin, the risks observed in the HMOs weresubstantially higher than the summary estimates of discontinuationrates reported in randomized clinical trials, which ranged from4 percent with niacin to 31 percent with the bile acid sequestrants.Substantial heterogeneity was found among the estimates of thediscontinuation rates reported in the trials, but those reportedin each randomized trial of bile acid sequestrants, niacin,or gemfibrozil were lower than the corresponding rates in theHMOs for comparable periods. Similarly, Thurmer et al.³² reporteda marked difference in effectiveness between antihypertensivetherapy in primary care settings and the benefits reported inrandomized clinical trials.

Although this study evaluated discontinuations of drug therapythat were initiated by the patient or the physician and didnot specifically assess overall adherence to a regimen of medication,the estimated discontinuation rates are similar to the 23 to50 percent frequencies of noncompliance in studies of therapyfor hypertension and other chronic diseases.³³^,³⁴^,³⁵^,³⁶ Long-termclinical trials of antihypertensive drugs have reported discontinuationrates of approximately 30 percent,³⁷^,³⁸ and community-basedstudies with one or more years of follow-up have reported dropoutrates of approximately 50 percent from antihypertensive carein private practice³⁹ and clinic⁴⁰^,⁴¹ settings.

The open-label studies we examined reported discontinuationrates similar to those obtained from the HMOs. Thus, althoughopen-label studies are generally considered inferior to randomizedtrials in the evaluation of therapeutic efficacy, such studiesmay reflect the success of therapy in primary care settingsmore accurately when drug discontinuation is taken as the measureof drug failure. Whether this is the result of less stringentpatient care or of differences in the study populations is uncertain.

Unlike previous studies that reported high frequencies of discontinuationof antihyperlipidemic drugs in primary care settings,⁴²^,⁴³^,⁴⁴our study used survival analysis to account for varying lengthsof follow-up. In this manner, we were able to include all theobservations, regardless of the length of follow-up, and toestimate the risk of drug discontinuation according to the durationof therapy. We also used this approach to assess specific causesof drug discontinuation, counting courses of drugs as censoredthat were terminated for reasons other than those used in thestudy. Our review of the medical records suggested that thereasons for discontinuation were often mixed, even when a predominantreason was cited. The adverse effects of a drug and its ineffectivenessmay not be independent factors in causing the discontinuationof the drug, and our analyses of the reasons for discontinuationare presented to permit examination of the balance among specificreasons, without our suggesting a relation of cause and effect.

Data from clinical trials on intolerance to drugs and on therapeuticfailures are likely to be more accurate than the informationwe could obtain from records of clinical practice. In clinicaltrials, information on drug discontinuation was collected prospectively,and more complete ascertainment was possible. In our cohortstudy, the use of the computerized files of the HMOs to identifypossible drug discontinuations may have led to an underascertainmentof the actual discontinuations. Reviewing the medical chartsfor a random sample of antihyperlipidemic treatments for whichthe computerized files showed no evidence of a drug discontinuationrevealed that according to the charts, 7 percent of the treatmentshad been discontinued (unpublished data). Thus, among the approximately1300 additional patients with no evidence of drug discontinuationfor whom a medical chart was not reviewed, additional drug discontinuationswere likely to have been missed. In addition, we excluded approximately100 patients from the study who were initially flagged by thecomputer as having potentially discontinued antihyperlipidemicdrug use; in these cases, the medical chart did not show adequatedocumentation of such use (unpublished data). All these sourcesof error would tend to reduce the apparent distinction betweenclinical trials and HMO practice, making our findings of substantialdifferences all the more striking.

Antihyperlipidemic agents are generally distributed withoutcost to patients in clinical trials. This factor was not, however,markedly different from the situation in the HMOs we studied.All HMO members included in the cohort study had insurance coveragefor prescription drugs and paid only a nominal copayment foreach prescription.

We also explored the influence of other characteristics of thestudy populations on the rates of discontinuation of antihyperlipidemicdrugs in order to determine plausible factors contributing tothe marked disparity in rates between the HMOs and the randomizedtrials. In the HMOs, the discontinuation rate was 33 percenthigher among women than among men, a difference entirely explainedby the fact that the rate of discontinuation due to the incidenceof adverse effects was 79 percent higher among women. Age hadno consistent influence on drug discontinuation. However, patientswho had previously discontinued therapy with an antihyperlipidemicdrug were more likely to discontinue subsequent therapy. Inthe long-term randomized clinical trials of lovastatin, theselection criteria were less stringent. Women were enrolled,as well as patients with various disease states and concomitantuse of nonstudy drugs, and the discontinuation rates estimatedin these trials were similar to those in the HMO populations.

Bias in patterns of prescribing the lipid-lowering drugs waslikely to be present in this cohort study, but such bias wouldnot discount the observed differences in rates between the randomizedtrials and the primary care settings. However, this bias preventslegitimate comparison of the agents within the HMO settingswith respect to safety and effectiveness. As has been noted,users of secondary agents at the HMOs were more likely to discontinuetherapy. However, patients in whom all other available agentshad failed might be more likely to continue receiving suboptimaltherapy.

The high frequency of discontinuation of antihyperlipidemicdrugs due to adverse effects and therapeutic ineffectivenessin our HMO population suggests that the discontinuation ratesreported in randomized clinical trials may not give an accuratereflection of the tolerability or effectiveness of therapy inthe general population. Whereas randomized clinical trials areoften regarded as the gold standard in the assessment of drugefficacy, they may provide inferior information with regardto certain outcomes. Reports from such trials may imply thatantihyperlipidemic agents have an overly optimistic successrate, thereby distorting the judgment of both practicing physiciansand the policy makers who assess the cost effectiveness of thesedrugs. Evaluations of cholesterol-lowering therapy have reportedthat early drug discontinuation has a substantial influenceon the cost of treatment.⁴⁵^,⁴⁶ Our findings suggest a need forfurther study of the effectiveness and tolerability of theseagents.

Supported in part by the Harvard Pharmacoepidemiology Teachingand Research Fund (with donations from Berlex Laboratories,Boehringer–Ingelheim Pharmaceuticals, the Burroughs WellcomeFund, the Ciba–Geigy Corporation, Hoffmann–LaRoche,ICI Pharmaceuticals Group, Eli Lilly, the Merck Foundation,and Pfizer), by a National Research Service Award (ST32 ES07067)from the National Institute of Environmental Health Sciences(to Dr. Andrade), by a grant (5 R01 HS07767-02) from the Agencyfor Health Care Policy and Research (to Dr. Testa), and by agrant from the Harvard Community Health Plan Foundation (toDr. Gottlieb).

We are indebted to Barbara Lewis, Ph.D., Jan Guilbert, R.N.,Maria Wennerberg, R.N., and Robert Astrella of the Fallon Clinicand to Emily Cain and James Livingston of HCHP and ChanningLaboratory for their assistance in the technical aspects ofdata collection at the two HMOs.

Source Information

From the Departments of Epidemiology (S.E.A., A.M.W.) and Biostatistics (M.A.T.), Harvard School of Public Health, Boston; Clinical Quality Management, Harvard Community Health Plan, Brookline, Mass. (L.K.G.); the Departments of Radiology and Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (N.K.H.); the Division of Cardiology, Fallon Clinic, Worcester, Mass. (G.M.S.); the Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Community Health Plan, and Channing Laboratory and the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (R.P.). Presented in part at the 10th International Conference on Pharmacoepidemiology, Stockholm, Sweden, August 30, 1994.

Address reprint requests to Dr. Walker at the Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115.

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Discontinuation of Antihyperlipidemic Drugs
Ellis P., Andrade S. E., Walker A. M.
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N Engl J Med 1995; 333:1082-1083, Oct 19, 1995. Correspondence

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