Cardiovascular Medication Use Following Percutaneous Coronary Intervention: The Australian Experience

Authors

  • Justin A. Cole,

    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
    2. Alfred Hospital, Melbourne, Vic., Australia
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  • Angela L. Brennan,

    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
    2. Alfred Hospital, Melbourne, Vic., Australia
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  • Andrew E. Ajani,

    Corresponding author
    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
    2. Royal Melbourne Hospital, Melbourne, Vic., Australia
    3. University of Melbourne, Melbourne, Vic., Australia
    • Correspondence

      A. E. Ajani, M.D., Department of Cardiology, Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, Vic. 3050, Australia.

      Tel.: +61-3-93295093;

      Fax: +61-3-9347-6760;

      E-mail: andrew.ajani@mh.org.au

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  • Bryan P. Yan,

    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
    2. The Chinese University of Hong Kong, Hong Kong, China
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  • Stephen J. Duffy,

    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
    2. Alfred Hospital, Melbourne, Vic., Australia
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  • Philippa Loane,

    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
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  • Christopher M. Reid,

    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
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  • Matias B. Yudi,

    1. Royal Melbourne Hospital, Melbourne, Vic., Australia
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  • Gishel New,

    1. Box Hill Hospital, Melbourne, Vic., Australia
    2. Eastern Health Medical School, Monash University, Melbourne, Vic., Australia
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  • Alexander Black,

    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
    2. Royal Melbourne Hospital, Melbourne, Vic., Australia
    3. Geelong Hospital, Melbourne, Vic., Australia
    4. Deakin University, Melbourne, Vic., Australia
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  • James Shaw,

    1. Alfred Hospital, Melbourne, Vic., Australia
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  • David J. Clark,

    1. Austin Hospital, Melbourne, Vic., Australia
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  • Nick Andrianopoulos

    1. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Vic., Australia
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Summary

Aims

Despite the guidelines, a “treatment gap” exists in the delivery of pharmacotherapy for secondary prevention. We aimed to analyze the trend in guideline-based medication usage following percutaneous coronary intervention (PCI) using the Melbourne Interventional Group (MIG) registry over a 6-year period (2005–2010).

Methods

The MIG registry prospectively collects demographical, clinical, and procedural characteristics of consecutive patients undergoing PCI. We assessed medication use (aspirin, clopidogrel, ACE inhibitors, angiotensin receptor blockers, beta-blockers, and lipid-lowering agents) at 30 days and 12 months in patients alive and able to provide the information.

Results

The cohort consists of 12,813 patients who underwent 14,787 consecutive interventional procedures. They comprised 76% males: 22% were elderly (≥75 years), 23% had diabetes, 2% had severe renal impairment, 2% had severe left ventricular dysfunction, 26% presented with STEMI, and 44% of patients received drug-eluting stent. Follow-up was complete for 97.8% of the cohort at 30 days (2.2% mortality) and 89.1% at 12 months (4% mortality). From 2005 to 2010, the percentage of patients taking all five classes of medications increased each year. In 2010 at 30 days, nearly 60% of patients took all five classes of medications, and by 12 months, 75% of patients were taking four or five classes of medications.

Conclusion

In conclusion, while the increasing use of cardiovascular medicines in an “at-risk” Australian cohort is encouraging, a treatment gap appears to still exist.

Introduction

A spectrum of cardiac medications including aspirin, clopidogrel, angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta-blockers (BB), and lipid-lowering agents (principally statins) is of proven benefit for patients with ischemic heart disease. These drugs form the basis of current management guidelines [1-3]. Despite these guidelines, a “treatment gap” exists in the delivery of quality secondary prevention [4-6].

Since its inception in 2004, the Melbourne Interventional Group (MIG) registry has collected comprehensive data on consecutive patients undergoing percutaneous coronary interventions (PCI), including medication use [7]. There are few Australian data available on medical secondary prevention in patients undergoing PCI. The MIG PCI cohort is relatively at high risk, as the majority of patients had an acute coronary syndrome as the indication for the index PCI. As an “at-risk” Australian population, we felt it would be useful to analyze medication usage following percutaneous coronary intervention (PCI) using the MIG data over a 6-year period (2005–2010).

Methods

The MIG registry prospectively collects demographical, clinical, and procedural characteristics of consecutive patients undergoing PCI, and its methods have been described previously [7]. Currently, six tertiary referral hospitals participate in data collection. Follow-up data are collected at 30 days and 12 months, either by telephone or by record review. Clinical events are validated by medical record review. We analyzed medication use at 30 days and 12 months following PCI in 12,813 patients who underwent 14,787 consecutive interventional procedures.

Prior to the commencement of the registry, a MIG database committee identified key data fields to collect, including pharmacotherapy. All Australian commercially available cardiovascular drugs are included in the MIG definition for drug categories. The medications reported in the registry include aspirin, clopidogrel (and more recently, prasugrel and ticagrelor), ACEi or ARB, BB, and statin (and other lipid-lowering agents) use. A combination of dual antiplatelet therapy (DAPT) was defined as the simultaneous use of aspirin and clopidogrel. More contemporary antiplatelet agents such as prasugrel and ticagrelor were not analyzed. ACEi or ARB use was combined in a single field (not differentiated). Statins were the only drugs where subclass was collected; however, nonstatin lipid-lowering agents are not reported in this analysis.

Medication use was further analyzed in selected patient groups including by gender, diabetics, severe renal impairment, age (≥75 years), severe impairment of left ventricular function, ST-elevation myocardial infarction (STEMI), and stent type. Yearly comparison for trend is made between medication usages from the start of the study (2005) until the study end (2010). Diabetics included those on oral hypoglycemic medications and/or insulin. Severe renal impairment was defined as an estimated glomerular filtration rate (eGFR) <30 ml/min. Severe left ventricular ejection fraction (LVEF) was defined as an LVEF <30%. Stent type was classified as bare-metal stent (BMS) or drug-eluting stent (DES). In general, clopidogrel was indicated for at least 30 days after BMS and at least 12 months after DES (i.e., DAPT with aspirin).

The study protocol was approved by the ethics committee at each participating hospital with approval for “opt-out” consent. This model has been recommended in clinical quality registries and is currently used in other Australian registries [8-10]. The MIG registry is coordinated by the Centre for Cardiovascular Research and Education in Therapeutics at Monash University in Melbourne, Australia. An independent audit was conducted annually at all enrolling sites by an investigator not affiliated with the institution. Twenty verifiable fields from 5% of patients enrolled from each site per annum were randomly audited and demonstrated an overall accuracy of 96.6%.

Categorical variables are presented as frequencies (%) and continuous variables as mean (standard deviation) or median (interquartile range) as appropriate. Variables were tested for linear trend across the years 2005–10 using Stata's nptrend command [11]. This is a nonparametric test for trend across ordered groups, which is an extension of the Wilcoxon rank-sum test. P-trend values <0.05 were considered to be statistically significant. Statistical analysis was conducted by an independent statistician using Stata/MP version 11.1 for Windows (StataCorp LP, College Station, TX, USA).

Results

The cohort consists of patients who underwent 14,787 consecutive interventional procedures. This group comprised 76% males, 22% were elderly (≥75 years), 23% had diabetes, 2% had severe renal impairment, 2% had severe LV dysfunction, 26% presented with a STEMI, and 44% of patients received DES. Follow-up was complete for 97.8% of the cohort at 30 days (2.2% mortality) and 89.1% at 12 months (4% mortality).

Medication use for all patients from 2005 to 2010 is shown in Table 1. The rate of adherence to all prescribed medications in this cohort has increased over the reported 6 years. Aspirin use is almost universal throughout the follow-up period. Clopidogrel use at 30 days remains very high, and the DAPT rates at 12 months continued to increase over the study period. The variable rate is multifactorial and heavily influenced by rate of DES use (which also fluctuated due to varying factors such as changing indications, cost, etc.).

Table 1. Frequency of use of medications: 2005–2010
 Total200520062007200820092010P-trend
  1. ACEi/ARB, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; BB, beta-blocker; DAPT, dual antiplatelet therapy.

Aspirin (%)
30 days97.495.696.797.198.298.898.3<0.01
12 months93.391.091.592.894.696.395.8<0.01
Clopidogrel (%)
30 days94.289.994.696.396.396.092.6<0.01
12 months64.657.563.664.164.371.370.9<0.01
DAPT (%)
30 days92.086.491.593.794.694.991.5<0.01
12 months60.050.657.558.760.268.768.1<0.01
BB (%)
30 days73.665.569.473.877.578.979.2<0.01
12 months66.959.862.869.571.871.969.9<0.01
ACEi/ARB (%)
30 days78.675.677.579.379.379.181.6<0.01
12 months77.674.476.978.280.278.079.6<0.01
Statin (%)
30 days94.091.593.394.194.895.795.5<0.01
12 months92.490.991.392.694.093.393.3<0.01

The use of BB, ACEi or ARB, and statins has been encouragingly high in this cohort. There has been a steady rise in use of all medication groups, analyzed yearly at both follow-up time points (Table 1, P for trend <0.01). The importance of BB and ACEi/ARB has been recognized by treating physicians. Almost universal statin use is reassuring given their impact on cardiovascular mortality.

The number of medications used at 30 days and 12 months over the reported years is shown in Figure 1. At both time intervals, most patients are taking either 4 or 5 of these guideline-indicated cardiovascular medications, with very few patients taking none or one medication. From 2005 to 2010, the percentage of patients taking all five medications increased each year. In 2010 at 30 days, nearly 60% of patients took all five medications, and by 12 months, 75% of patients were taking four or five medications.

Figure 1.

(A) Frequency (%) of number of medications (aspirin, clopidogrel, BB, ACEi/ARB, statin) taken at 30 days. (B) Frequency (%) of number of medications (aspirin, clopidogrel, BB, ACEi/ARB, statin) taken at 12 months.

Medication usage over time for selected at-risk populations is shown for 30-day and 12-month follow-up, respectively (Tables 2 and 3). Females have often been undertreated in cardiovascular trials compared with males. While female medication rates were lower in most instances at both follow-up periods, it was noted that there was increase in use of all drug classes from 2005 to 2010, with a window for further improvement. The rate of medication use in the elderly (≥75 years) was almost equivalent to the overall cohort. Given the importance of secondary prevention in this high-risk population, the 2010 adherence rates remain promising.

Table 2. Medication use at 30 days (selected subgroups)
 Aspirin (%)Clopidogrel (%)DAPT (%)BB (%)ACEi/ARB (%)Statins (%)
  1. ACEi/ARB, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; BMS, bare-metal stent; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; STEMI, ST-segmental elevation myocardial infarction.

  2. All P for trend <0.05 from 2005 to 2010, unless indicated with *. Data for 2006–2009 not shown.

Year200520102005201020052010200520102005201020052010
Total95.698.389.992.686.491.565.579.275.681.891.595.5
Male (75%)95.898.689.392.686.091.865.779.676.182.192.596.3
Female (25%)95.097.591.492.887.490.465.078.174.280.888.793.3
Age >75 years (22%)93.296.986.792.481.890.159.676.075.579.785.992.5
Diabetes (24%)95.198.089.392.185.390.465.678.580.781.8*91.194.0
Renal impairment eGFR <30 ml/min (3%)92.796.4*85.189.5*78.887.5*71.282.1*66.749.1*80.389.1*
LVEF <30% (2%)87.510081.392.077.19268.892.091.768.087.5*92.0*
STEMI (27%)93.391.788.891.7*82.990.880.189.185.489.7*94.797.2
Stent type: BMS (51%)94.993.186.993.082.99267.380.875.783.393.396.1
DES (44%)96.498.995.697.092.596.163.578.075.281.389.995.4
Table 3. Medication use at 12 months (selected subgroups)
 Aspirin (%)Clopidogrel (%)DAPT (%)BB (%)ACEi/ARB (%)Statins (%)
  1. ACEi/ARB, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; STEMI, ST-segmental elevation myocardial infarction; BMS, bare-metal stent; DES, drug-eluting stent.

  2. All P for trend <0.05 from 2005 to 2010, unless indicated with *. Data for 2006–2009 not shown.

Year200520102005201020052010200520102005201020052010
Total91.095.857.570.950.668.159.869.974.479.690.993.3
Male (76%)90.995.957.969.951.267.259.971.874.880.291.994.5
Female (24%)91.195.556.573.949.270.859.664.673.277.988.190.0
Age >75 years (22%)86.793.258.965.948.162.458.264.572.478.0*85.389.5
Diabetes (23%)89.994.666.078.457.473.960.674.078.980.1*91.493.3*
Renal impairment eGFR <30 ml/min (2%)81.097.070.269.7*53.669.7*64.381.8*63.648.5*80.090.9
LVEF <30% (2%)84.890.5*56.575.043.570.069.685.791.381.0*87.076.2*
STEMI (26%)*92.096.857.768.151.466.271.878.981.287.393.095.4
Stent type: BMS (51%)91.395.746.657.540.854.860.070.073.780.790.493.8
DES (44%)90.796.968.389.260.586.859.270.374.878.490.893.3

Discussion

There is overwhelming evidence that use of secondary prevention medication after PCI reduces the risk of cardiovascular events and re-hospitalizations and improves survival [1]. Our study documents the increasing use of five guideline-recommended cardiovascular medicines in a large “at-risk” Australian cohort. While medication use has largely increased for each individual medication over the 6-year period, a treatment gap remains.

While all registries are unique, with subtle differences, our results compare favorably to other established international cohorts. We note that the MIG registry has higher 12-month rates of statin use (93% vs. 87%) and aspirin use (96% vs. 87%) and lower rates of BB use (70% vs. 81%) compared with the European APTOR registry [12]. The EUROASPIRE III survey analyzed a cohort of patients presenting with myocardial infarction, revascularized with PCI or cardiac bypass surgery. MIG 2007 medication use at 12 months was similar to this EUROASPIRE cohort (antiplatelet use 92.8% vs. 91%, BB use 69.5% vs. 71%, ACEi/ARB use 78.2% vs. 71%, and statin use 92.6% vs. 78% were clearly higher) [13],. In a large Korean registry postmyocardial infarction in the period 2005–2008, 72.7% of patients were on BB, 81.5% on ACEi/ARB, and 77.2% on statins, comparable with our earlier results [14]. Trends in German patients across EUROASPIRE 1 (1995–6), II (1999–2000), and III (2006–7) show increased prescribing of antihypertensives (80.4%, 88.6%, 94.3%) and lipid-lowering drugs (35%, 67.4%, 87%), replicating our positive trends in medication usage over time [15].

We have identified near universal use of aspirin by 2010. The role of DAPT with clopidogrel has recently been the topic of great debate [16]. The general consensus of at least 12-month therapy after DES deployment has been challenged, with some advocating only 6-month therapy [17]. Whatever ideal therapy eventuates, we noticed a 30% discontinuation rate of clopidogrel between 30 days and 12 months (2010), despite the general recommendations at the time of continuing therapy. Mauri et al. [18] are evaluating the question of 12 months versus 30 months of DAPT in the ongoing DAPT study. Further, a UK study (in the time frame 2003–2009) showed that discontinuing clopidogrel 12 months after either STEMI or NSTEMI had an adjusted HR for death or nonfatal MI of 2.62 compared with patients persisting with treatment [19]. The ultimate goal is to bridge the persistent “gap” in pharmacotherapy delivery based on clinical evidence [20]. In a recent study in Australia, this gap remains ever-present and extends to secondary prevention targets [21]. After a cardiac event, the majority of patients did not achieve recommended targets for waist girth, blood pressure, total cholesterol, HDL cholesterol, and physical activity after 6 weeks.

Insight may be attained from subgroup analyses. Females are under prescribed pharmacotherapy and are even less likely to reach clinical targets than males [22, 23]. Diabetics have under-utilized these medications, and this clearly adds as an important factor to poorer cardiovascular outcomes [24]. The increased use of secondary prevention medications for patients following STEMI has been found in similar Australian cohorts [25]. These increases, together with increased use of emergency PCI, were associated with a fall in in-hospital events and rates of re-admissions. Patients with the greatest benefit of medical therapy such as those with renal dysfunction and poor left ventricular function are often undertreated or cannot tolerate optimal therapy. Improvement in prescribing habits (therapeutic inertia) and patient adherence to medical therapy are multifactorial. Clear benefits exist for patient education about their cardiac status, attendance at specialist clinics, participation in a cardiac rehabilitation program, and follow-up in a registry program such as the MIG registry [26, 27].

While prospectively collected, this study has limitations related to registry data. Self-reporting of medications does not guarantee that tablets were consistently taken. These data pertain only to live patients, as medication data are not collected in deceased patients. Newer medications such as novel antiplatelet agents were not included as they had not been in use for the entire study period, thus limiting trend analysis. Finally, we have not reported on other lipid-lowering classes of medications such as fibrates or ezetimibe, which might have increased our percentage of guideline-indicated treatment in patients intolerant of statins.

Conclusions

Secondary prevention medication after percutaneous intervention reduces mortality and recurrent cardiovascular events. The Melbourne Interventional Group registry has shown increasing use of recommended cardiovascular medicines in an “at-risk” Australian cohort over a 6-year period. While guideline-indicated medication use has largely increased, a treatment gap remains. This warrants further investigation of strategies directed toward clinicians and patients to further improve guideline adherence.

Acknowledgments

Melbourne Interventional Group DATA MANAGEMENT CENTRE, CCRE, Monash University: Prof Chris Reid, Dr Nick Andrianopoulos, Ms Angela Brennan, Ms Philippa Loane. MIG STEERING COMMITTEE: Prof Chris Reid, A/Prof Andrew Ajani, Dr Stephen Duffy, Dr David Clark, A/Prof Gishel New, A/Prof Alexander Black, Dr Nick Andrianopoulos, Dr Ernesto Oqueli, Dr Rob Lew, Ms Angela Brennan. The following investigators, data managers, and institutions participated in the MIG database: Alfred Hospital: SJ Duffy, JA Shaw, A Walton, A Dart, A Broughton, J Federman, C Keighley, C Hengel, KH Peter, D Stub, R Sharma, J O'Brien, R Vandernet Austin Hospital: DJ Clark, O Farouque, M Horrigan, J Johns, L Oliver, J Brennan, R Chan, G Proimos, T Dortimer, B Chan, V Nadurata, R Huq, D Fernando, K Charter, L Brown, A Al-Fiadh, H Sugumar, R Spencer, J Ramchand. Ballarat Base Hospital: E Oqueli, F Grieg, C Barry. Box Hill Hospital: G New, L Roberts, M Rowe, G Proimos, Y Cheong, C Goods, D Fernando, D Tong, A Baradi, D Jackson, P Naidu, J Beale. Frankston Hospital: R Lew, G Szto, R Teperman, R Huq. Geelong Hospital: A Black, M Sebastian, T Yip, C Hiew, J Dyson, T Du Plessis, B McDonald, L Duff. Monash University: H Krum, C Reid, N Andrianopoulos, AL Brennan, P Loane, L Curran, D Dinh, BP Yan. Royal Melbourne Hospital: AE Ajani, R Warren, D Eccleston, J Lefkovits, R Iyer, R Gurvitch, W Wilson, M Watts, M Brooks. Dr. Duffy's work was supported by an NHMRC Program Grant to the Alfred and Baker Medical Unit. Prof Reid's work was supported by an NHMRC Senior Research Fellowship and NHMRC Program Grant.

Funding

The Melbourne Interventional Group acknowledges funding from Abbott, Astra-Zeneca, Biotronik, Boston Scientific, Bristol-Myers Squibb, Cordis Johnson & Johnson, CSL, Medtronic, MSD, Pfizer, Sanofi-Aventis, Servier, and Schering-Plough. These companies do not have access to data and do not have the rights to review manuscripts or abstracts before publication.

Conflict of Interest

The authors declare no conflict of interest.

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