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(Circulation. 2005;112:1296-1300.)
© 2005 American Heart Association, Inc.

Health Services and Outcomes Research

Impact of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22/Reversal of Atherosclerosis With Aggressive Lipid Lowering Trials on Trends in Intensive Versus Moderate Statin Therapy in Ontario, Canada

Peter C. Austin, PhD; Muhammad M. Mamdani, PharmD, MA, MPH

From the Institute for Clinical Evaluative Sciences (P.C.A., M.M.M.), Department of Public Health Sciences (P.C.A.), Faculty of Pharmacy (M.M.M.), and Department of Health Policy, Management and Evaluation (P.C.A., M.M.M.), University of Toronto.

Correspondence to Dr Peter C. Austin, Institute for Clinical Evaluative Sciences, G1 06, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada. E-mail peter.austin{at}ices.on.ca

Received December 22, 2004; revision received May 26, 2005; accepted June 2, 2005.

	Abstract

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Background— In March 2004, the Reversal of Atherosclerosis With Aggressive Lipid Lowering (REVERSAL) trial demonstrated that intensive lipid-lowering therapy (atorvastatin 80 mg/d) reduced progression of coronary atherosclerosis compared with moderate lipid-lowering therapy (pravastatin 40 mg/d). The following month, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI 22) study demonstrated the superiority of intensive (atorvastatin 80 mg/d) versus moderate (pravastatin 40 mg/d) lipid-lowering therapy for reducing death or cardiovascular events in patients suffering from an acute coronary syndrome. We sought to determine the impact of these 2 trials on trends in intensive versus moderate statin therapy in Ontario, Canada.

Methods and Results— This is a retrospective time-series analysis of statin prescribing between June 1997 and September 2004 in Ontario, Canada, for all residents age 65 years and older. The publication of the PROVE IT–TIMI 22 and REVERSAL trials was associated with a sustained and statistically significant increase in the number of prescriptions dispensed for atorvastatin 80 mg (range, 272 to 635 additional prescriptions per month), whereas the number of prescriptions filled for pravastatin 40 mg did not change. Similarly, it resulted in a temporal increase in the relative market share of atorvastatin at a dose of 80 mg versus that of atorvastatin at a dose of 40 mg. However, the proportion of simvastatin prescriptions for 80 mg relative to 40 mg did not change over time, implying a drug-specific effect rather than a class effect in prescribing practice.

Conclusions— The publication of the PROVE IT–TIMI 22 and REVERSAL trials resulted in a significant sustained increase in the use of intensive compared with moderate statin therapy. This shift was evident primarily in an increased use of high-dose atorvastatin and did not appear to be generalizable to other statins.

Key Words: cholesterol • drugs • lipids • pharmacology • trials

	Introduction

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Well-publicized clinical trials can have a significant impact on the utilization rates of medications examined in the trial. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) concluded that thiazide-type diuretics should be the first-step antihypertensive therapy, compared with either angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers.¹ This was followed by an immediate increase in the relative market share of diuretics compared with ACE inhibitors in Ontario.² The Women’s Health Initiative study concluded that overall health risks exceeded benefits from the use of estrogen plus progestin.³ This resulted in an immediate and substantial decrease in the prevalence of estrogen replacement therapy use among elderly Ontario women.⁴

The Reversal of Atherosclerosis With Aggressive Lipid Lowering (REVERSAL) trial, published on March 3, 2004, demonstrated that for patients with coronary heart disease, intensive lipid-lowering therapy reduced progression of coronary atherosclerosis compared with moderate therapy.⁵ One month later, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI 22) trial (published on April 8, 2004) demonstrated that among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provided greater protection against death or major cardiovascular events than did a standard regimen.⁶ In both trials, standard therapy consisted of 40 mg/d of pravastatin, whereas intensive therapy consisted of 80 mg/d of atorvastatin. Previous studies have demonstrated the impact of randomized clinical trials on the trends in prescribing of a class of medications. However, relatively little is known about how the publication of clinical evidence affects prescribing trends within a class of medications. The nearly simultaneous publication of 2 randomized clinical trials that demonstrated the superiority of intensive lipid-lowering therapy compared with moderate lipid-lowering therapy provided an opportunity to examine the impact of publication on trends in the prescribing of different statins. Hence, the objective of the present study was to examine the impact of the publication of these 2 trials on trends in intensive versus moderate statin therapy in the province of Ontario.

	Methods

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We studied claims for statins to Ontario’s universal Drug Benefit program for seniors (ODB) between June 1, 1997 (the month atorvastatin was added to the ODB formulary), and September 30, 2004. The ODB tracks medication use by all 1.4 million residents of Ontario older than 65 years. The following statins are available on the ODB formulary at a dose of 40 mg: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin, and the following are available at a dose of 80 mg: atorvastatin and simvastatin. Cerivastatin was not included in the analysis because of its withdrawal from the market.

For each month of each year, we determined the number of statin prescriptions filled by residents of Ontario age 65 years and older. The relative market share of a given formulation of statin compared with a different formulation was defined to be the percentage of all prescriptions of either formulation that were attributed to the given formulation.

Our primary analysis examined the impact of the publication of the PROVE IT–TIMI 22 and REVERSAL trials on trends in the monthly number of prescriptions for the 2 therapies studied in PROVE IT–TIMI 22/REVERSAL (atorvastatin 80 mg/d and pravastatin 40 mg/d). These analyses were restricted to the period beginning in April 2002, when atorvastatin 80 mg/d was introduced to the ODB formulary. The REVERSAL trial results were published in the Journal of the American Medical Association on March 3, 2004 (along with an associated editorial⁷), whereas the PROVE IT–TIMI 22 trial results were published in the New England Journal of Medicine on April 8, 2004.⁶ The results of each trial were publicized before their publication in their respective journals. The results of the REVERSAL study were released at the American Heart Association conference in November 2003, whereas the results of the PROVE IT–TIMI 22 study were presented on March 8, 2004, at the American College of Cardiology meeting and released online on the New England Journal of Medicine’s website at the same time.

Five secondary analyses were then conducted to examine trends in market shares for different statin formulations. First, for both atorvastatin and simvastatin separately, we determined the relative market share of a dose of 40 mg/d versus that of a dose of 80 mg/d. For simvastatin, this analysis was limited to the period beginning in April 2000, when simvastatin 80 mg/d was introduced to the ODB formulary, whereas for atorvastatin, this analysis was limited to the period beginning April 2002. Second, we examined trends in the monthly relative market share of any statin at a dose of 40 mg/d versus that of any statin at a dose of 80 mg/d. These analyses were restricted to the period beginning in September 2000, when the first dose of 80 mg/d statin was introduced into the ODB formulary. Third, because of the nonequivalency in dose potency across different statins,⁸ we examined trends in the relative market share of the strongest dosage available for a given statin versus all other dosages of that statin. This analysis was restricted to the following statins: atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. Rosuvastatin was not examined in these analyses because of sparse use, resulting in unstable estimates. Fourth, we examined trends in the monthly number of prescriptions filled for atorvastatin at a dose of 40 mg/d. This analysis was restricted to the period beginning in August 1997. Fifth, we examined trends in the monthly number of prescriptions filled for any statin.

Finally, to provide addition information, we determined the number of prescriptions filled for each statin, regardless of dose.

To examine changes in the prescribing of statins over time, we used time series analysis. Time series analysis,⁹ a collection of techniques for modeling autocorrelation in temporally sequenced data, was conducted using exponential smoothing models and autoregressive, integrated, moving average (ARIMA) models to examine temporal changes in statin-prescribing patterns. For the primary analysis, 2 intervention parameters, incorporated by use of ramp functions,¹⁰ were added to the ARIMA model. The first intervention parameter accounted for the prepublication release of REVERSAL, and the second intervention parameters accounted for the publication of the REVERSAL study, the prerelease of the PROVE IT–TIMI 22 study, and the actual publication of the PROVE IT–TIMI 22 study. Because of the close proximity of these 3 events, only 1 interventional term was added to account for them all. The statistical significance of each intervention was assessed by examining the statistical significance of the ß parameter estimates corresponding to the intervention terms.⁹ Model-derived projections and their 95% confidence intervals for the months after April 2004 were compared with actual utilization estimates. For the ARIMA model, stationarity was assessed using the autocorrelation function and the augmented Dickey-Fuller test,¹¹ whereas the autocorrelation, partial autocorrelation, and inverse autocorrelation functions were assessed for model parameter appropriateness and seasonality, and the presence of white noise was assessed by examining the autocorrelations at various lags using the Ljung-Box ² statistic.¹²

	Results

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Figures 1 and 2 describe trends in the monthly number of prescriptions filled for atorvastatin 80 mg/d and pravastatin 40 mg/d, respectively. Both the release of the REVERSAL trial results at American Heart Association meeting in November 2003 and the publication of the PROVE IT–TIMI 22 study in April 2004 were associated with a statistically significant increase in the number of prescriptions for high-dose atorvastatin (P=0.0058 and P<0.0001, respectively). The publication of REVERSAL and PROVE IT–TIMI 22 resulted in a significant increase in the number of prescriptions filled for high-dose atorvastatin (80 mg) in the 6 months after publication (P<0.0001 for each month). In the 6 months after the publication of the trials, the number of prescriptions filled for high-dose atorvastatin was 28.7%, 43.1%, 46.5%, 57.7%, 48.4%, and 54.1%, respectively, greater than predicted (this corresponded to an additional 272, 440, 509, 611, 561, and 635 additional prescriptions dispensed for high-dose atorvastatin, compared with predicted). In contrast to this, neither the release of the REVERSAL trial nor the publication of the PROVE IT–TIMI 22 trial had a statistically significant impact on the number of prescriptions filled for pravastatin 40 mg (P=0.7947 and 0.7363, respectively). Similarly, the observed number of prescriptions filled was not significantly different from that predicted (P>0.44 for each month).

View larger version (21K): [in this window] [in a new window]   Figure 1. Monthly prescriptions for atorvastatin 80 mg/d in Ontario, Canada.

View larger version (21K): [in this window] [in a new window]   Figure 2. Monthly prescriptions for pravastatin 40 mg/d in Ontario, Canada.

Figure 3 describes trends in the monthly relative market share of a dose of 80 mg compared with that of a dose of 40 mg for atorvastatin and simvastatin separately. Before April 2004, the relative market share of atorvastatin at a dose of 80 mg was increasing compared with that of atorvastatin at a dose of 40 mg. However, the relative market share in the months after the publication of the trial was significantly greater than predicted. In the 6 months after the publication of the trial, the observed relative market share of atorvastatin at a dose of 80 mg was, respectively, 11.4%, 23.4%, 22.4%, 21.4%, 21.4%, and 17.7% greater than predicted. For each of the 6 months after the publication of the trial, the observed relative market share was statistically significantly greater than predicted (P0.03 for each month). A comparable effect was not observed for simvastatin (P>0.63 for each month).

View larger version (26K): [in this window] [in a new window]   Figure 3. Relative market share of 80- vs 40-mg dose for atorvastatin and simvastatin.

Before the publication of the trials, the relative market share of any statin at a dose of 80 mg versus that of any statin at a dose of 40 mg was increasing. However, the relative market share in the months after the publication of the trial was significantly greater than predicted. In the 6 months after the publication of the trial, the observed relative market share of statins at a dose of 80 mg compared with that at a dose of 40 mg was, respectively, 9.6%, 21.7%, 20.2%, 22.5%, 24.0%, and 23.1% greater than predicted. For each of the 6 months after the publication of the trial, the observed relative market share was statistically significantly greater than predicted (P<0.0028 for each month).

The publication of the PROVE IT–TIMI 22 and REVERSAL trials was associated with a statistically significant and sustained effect on the relative market share of an 80-mg dosage of atorvastatin versus the use of all other strengths of atorvastatin. The relative market share of the use of atorvastatin at a dose of 80 mg was 14.5%, 30.8%, 31.5%, 32.1%, 33.8%, and 31.2%, respectively, greater than predicted (P<0.0001 for each month). Comparable results were not observed for the remaining statins (with the exception for 1 month of the 6 for simvastatin).

The publication of the PROVE IT–TIMI-22 and REVERSAL trials was associated with a statistically significant increase in the number of prescriptions dispensed for atorvastatin at a dose of 40 mg in 5 of the 6 months after the publications of the trials. In the 6 months after the publications of the trials, the number of prescriptions dispensed was 935, 434, 1444, 1554, 2293, and 2241, respectively, greater than predicted by the model. This corresponds to relative increases of 6.3%, 2.8%, 8.6%, 9.1%, 13.3%, and 12.3%, respectively, greater than predicted (P=0.0002; P=0.1110; P<0.0001; P=0.0001; P<0.0001; and P<0.0001 for each of the 6 months, respectively). In contrast, the publication of the PROVE IT–TIMI-22 and REVERSAL trials did not have a statistically significant impact on the total number of statin prescriptions dispensed in any of the 6 months after the publication of the trials (P>0.31 for each of the 6 months). The relative increase in the number of prescriptions dispensed compared with that predicted by the model varied from a low of –2.9% to a high of 3.2% in the 6 months after the publication of the trials.

The monthly number of prescriptions filled for each statin, regardless of dose, is described in Figure 4.

View larger version (22K): [in this window] [in a new window]   Figure 4. Trends in the market share of different statins in Ontario, Canada.

	Discussion

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The publication of the REVERSAL and PROVE IT–TIMI 22 trials had a significant impact on the prescribing of atorvastatin in Ontario, Canada. First, the monthly number of prescriptions filled for high-dose atorvastatin (80 mg/d) increased after publication of the trials, whereas the number of prescriptions filled for moderate-dose pravastatin did not change. Furthermore, the relative use of atorvastatin at a dose of 80 mg compared with that of atorvastatin at a dose of 40 mg increased after publication of the trial. However, a comparable relative change in the use of simvastatin at a dose of 80 mg compared with that of simvastatin at a dose of 40 mg was not observed. Finally, there was a noted shift toward high-dose use of atorvastatin compared with low- or moderate-dose atorvastatin. This effect was not noted for other statin formulations. The interpretation of this finding is complicated by the different potencies of the available statin drugs,⁸ but it implies that changes in physicians’ prescribing practices were limited to the drug examined in the specific clinical trial rather than intensifying dosing of other statin therapies.

The nearly simultaneous publications of the REVERSAL and PROVE IT–TIMI 22 trials provide an important opportunity to examine the impact of evidence from randomized controlled trials on physician prescribing patterns. Both trials compared patients treated with high-dose atorvastatin with those treated with moderate-dose pravastatin. The first study compared the impact of therapy on intermediary outcomes (progression of coronary atherosclerosis), whereas the second compared the impact of therapy on clinical outcomes (death or major cardiovascular events). Their publication, within 36 days of each other, provided evidence from 2 independent studies of the superiority of aggressive lipid-lowering therapy. Our study describes the confluence of well-publicized and -promoted mechanistic evidence (REVERSAL) and hard evidence on clinical outcomes (PROVE IT–TIMI 22) leading to a rapid change in the prescription of high-dose atorvastatin.

The prepublication release of medical research is a contentious issue.^13,14 In the present study, we observed that the prepublication release of the REVERSAL trial findings was associated with a modest but statistically significant increase in the number of prescriptions filled for high-dose atorvastatin. This finding mirrors that of Gross et al,¹⁵ who demonstrated that the prepublication dissemination of carotid endarterectomy trials was associated with rapid and substantial changes in the rate of carotid endarterectomy.

The present study adds to the growing body of literature demonstrating that dissemination of results from randomized trials can have a substantial impact on physicians’ prescribing patterns of the medications in question. Lamas et al¹⁶ demonstrated that the Physicians’ Health Study increased the use of aspirin before myocardial infarction among patients enrolled in the SAVE study, and publication of the Second International Study of Infarct Survival (ISIS-2) increased the use of aspirin after myocardial infarction. Furthermore, publication of the Multicenter Diltiazem Postinfarction Trial was associated with decreased use of calcium antagonists. Juurlink et al¹⁷ demonstrated that the publication of the Randomized Aldactone Evaluation Study (RALES) resulted in a significant increase in the rate of prescription of spironolactone. Several studies demonstrated that prescriptions for hormone replace therapy decreased substantially after the publication of the Women’s Health Initiative study.^4,18,19 Austin et al² reported that the publication of the ALLHAT trial results resulted in a significant increase in prescribing of thiazide-type diuretics, and Stafford et al²⁰ demonstrated that the early termination of the doxazosin mesylate arm of the study resulted in modest, yet statistically significant declines in the use of doxazosin and other -blockers. Majumdar et al²¹ demonstrated that the publication of the Heart Outcomes Prevention Evaluation (HOPE) was associated with a significant increase in the use of ramipril, whereas the publication of the RALES trial resulted in a more modest increase in the use of spironolactone. The impact of the HOPE trial on ramipril prescribing was also documented by Tu et al.²²

There are several limitations to our study. First, our data were limited to those over the age of 65 years and thus are not representative of the entire Ontario population. However, this is balanced by the fact that the data are population-based, providing coverage for all elderly residents in Ontario, Canada’s largest province. Second, we did not have information about the indications for which statins were prescribed; in particular, we did not know which of these patients had established coronary heart disease, the population studied in both PROVE IT–TIMI 22 and REVERSAL. However, because several of our analyses were based on trends in relative market share, this is unlikely to have an impact on the conclusions. Third, we were unable to account for temporal influences beyond the publication of the results of the trials. In particular, we were unable to account for changes in drug company promotion patterns. Pharmaceutical detailing has been demonstrated to result in an acceleration of the uptake of medications.²¹ Fourth, because of the study design and the relatively low monthly number of incident statin users, we were unable to definitively determine whether the trends that we observed were a result of an increase in the number of incident statin users who were being placed on high-dose atorvastatin or whether they were because of prevalent statin users’ changing therapy.

In conclusion, this study demonstrated that well-designed and well-publicized trials can have a significant impact on the prescribing patterns of the medications studied in the trial.

	Acknowledgments

 
The Institute for Clinical Evaluative Sciences is supported in part by a grant from the Ontario Ministry of Health and Long-Term Care. The opinions, results, and conclusions are those of the authors, and no endorsement by the Ministry of Health and Long-Term Care or by the Institute for Clinical Evaluative Sciences is intended or should be inferred. Dr Austin is supported in part by a New Investigator award from the Canadian Institutes of Health Research (CIHR). Dr Mamdani is supported by a New Investigator award from the New Emerging Teams of the CIHR. The authors thank the 3 anonymous reviewers for their comments, which greatly improved the manuscript.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 112/9/1296    most recent CIRCULATIONAHA.104.531582v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Austin, P. C. Articles by Mamdani, M. M. Search for Related Content PubMed PubMed Citation Articles by Austin, P. C. Articles by Mamdani, M. M. Related Collections Health policy and outcome research Cardiovascular Pharmacology Primary prevention Secondary prevention