UMPIRE: Fixed-dose combination in patients at high cardiovascular risk

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Macrovascular Residual Risk Studies

5 December 2013

Use of a fixed dose combination therapy targeting blood pressure, cholesterol and platelet control offers the possibility of concomitant control of risk factors and improved adherence in patients with or at high risk of cardiovascular disease (CVD).

Thom S, Poulter N, Field J et al; UMPIRE Collaborative Group. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA 2013;310:918-29.

STUDY SUMMARY

Objective:

Fixed-dose combination (FDC) therapy offers the possibility of overcoming shortfalls between at-risk patients requiring polypharmacotherapy and those adequately treated, especially in low- and middle-income countries with limited healthcare budgets. FDC therapy also has the potential advantage of improved adherence with treatment. However, so far only short-term trials of cardiovascular FDC therapy have been undertaken. The UMPIRE study investigated whether FDC therapy including aspirin, statin, and two blood pressure‚Äìlowering agents improved long-term adherence and control of systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) in patients with or at high risk of CVD while simultaneously providing antiplatelet therapy.

Study design:

Randomised, open-label, blinded-endpoint clinical trial comparing a FDC-based treatment strategy compared with usual care in centres in India, England, Ireland, and the Netherlands. There were two FDC therapies:
‚Ä¢ Aspirin 75 mg; simvastatin 40 mg; lisinopril 10mg; and atenolol 50 mg,
or
‚Ä¢ Aspirin 75 mg, simvastatin 40 mg; lisinopril 10 mg; and hydrochlorothiazide 12.5 mg Subjects were randomized to FDC or usual care in a 1:1 ratio, with allocation stratified by study site and the presence or absence of established CVD using a web-based clinical data management system For the FDC group, physicians had the option of initiating additional treatments, stopping the FDC and starting treatment with separate medications, or switching the FDC treatments. Subjects were enrolled between July 2010 and July 2011 and follow-up concluded in July 2012.

Study population:

Subjects aged ‚â•18 years with high CV risk, defined as either established CVD (history of coronary heart disease, ischaemic cerebrovascular disease, or peripheral vascular disease) or an estimated 5-year CVD risk of ‚â•15% were eligible for the study. The risk score included age, sex, SBP, ratio of total to high-density lipoprotein cholesterol (HDL-C), diabetes, smoking, with a 5% adjustment for people from India. Subjects had to have no contraindications for the components of at least 1 of 2 FDC treatments.

Of 2,138 subjects screened, 2,004 were subsequently randomized (1,000 in India and 1,004 in Europe. Of 1,002 subjects randomized to the FDC group, physicians started therapy with FDC version 1 for 589 (58.8%) and FDC version 2 for 413 (41.2%). Baseline characteristics were similar in the two groups; 88% had CVD, 82% were male and 28% had diabetes. At baseline, 91.4% were receiving antiplatelet therapy (n=1,832), 87.8% were receiving a statin (n=1,760), and 92% were receiving blood pressure lowering therapy (n=1,862). Mean BP was 137/78 mmHg and LDL-C was 91.5mg/dL (2.4 mmol/L).

Primary variable:

There were 2 main outcome measures:
‚Ä¢ Adherence to medication (self-reported current use of antiplatelet, statin, and ‚â•2 BP-lowering therapies, defined as taking the medication for at least 4 days during the week preceding the visit) and
‚Ä¢ Changes in SBP and LDL-C from baseline to end of study

Secondary variables:

Secondary outcomes included adherence at 12months, reasons for stopping CV medications, quality of life, serious adverse events, changes in total cholesterol, HDL-C, triglycerides, and creatinine from baseline to 12 months and end of study and CV events

Methods:

Eligible subjects attended the clinic at randomisation, at 12 months, and at the end of the study, and were followed-up by telephone or clinic visit at 1, 6 and 18 months. Blood pressure and fasting lipids were measured at baseline, 12 months, and the end of the study.

Self-reported adherence to all medications was recorded as the number of days medication was taken in the week prior to the visit. Subjects were also asked about barriers to adherence, quality of life (measured using the self-administered EQ-5D questionnaire), CV and other serious adverse events, and reasons for stopping CV medications (if appropriate).

Results:

The median duration of follow-up was 15 months (interquartile range, 12-18 months).

At the end of the study, treatment with FDC therapy:
‚Ä¢ improved adherence compared with usual care (86% versus 65% p<0.001) and
‚Ä¢ produced incremental reductions in LDL-C of 4.2 mg/dL (0.11 mmol/L) and SBP of 2.6 mmHg (p<0.001 for each analysis) compared with usual care (Table 1).

Table 1. Summary of primary outcomes

	FDC (n=1,002)	Usual care (n=1,002)	Treatment effect (95% CI)*	P-value
Adherence	829/961 (86%)	621/960 (65%)	1.33 (1.26 to 1.41)	<0.001
Mean LDL-C, mg/dL	84.2 (82.5-85.8)	88.4 (86.7-90.0)	‚àí4.2 (‚àí6.6 to ‚àí1.9)	<0.001
Mean SBP, mmHg	129.2 (128.1-130.2)	131.7 (130.7-132.8)	‚àí2.6 (‚àí4.0 to ‚àí1.1)	<0.001

Treatment effect was reported as relative risk for adherence and mean treatment difference for LDL-C and SBP There were no significant differences between the groups for changes in total cholesterol, triglycerides or HDL-C. Diastolic blood pressure was also incrementally reduced with FDC therapy compared with usual care (by 2.5 mmHg, p<0.001).

There were no significant differences in serious adverse events between the groups. CV events were reported for 50 (5%) subjects in the FDC group versus 35 (3.5%) subjects in the usual care group (relative risk 1.45; 95%CI 0.94-2.24; p=0.09). A similar number of deaths occurred in each group (17 in the FDC group vs 15 in the usual care group; RR, 1.13; 95%CI, 0.57-2.26; p = 0.72).

Authors‚Äô conclusion:

Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control versus usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C.

COMMENT

CVD is the leading cause of death and disability world-wide. However, whereas developed regions have seen a steady decline in CVD prevalence as a result of improved implementation of preventive strategies and new drug treatments, in developing regions, CVD has increased. Indeed, data from the World Health Organization show that nearly 80% of deaths due to CVD and diabetes occur in low- and middle income countries.(1) Thus, CVD accounts for a larger proportion of healthcare expenditure in these countries than in developed regions, highlighting the need for a re-thinking of strategies aimed at simplified delivery of low-cost effective treatment, ideally targeting multiple major CV risk factors to reduce this burden.

FDC therapy for primary or secondary prevention has been discussed for over a decade.(2) FDC involving generic medicines would potentially offer a number of advantages, specifically improved adherence, a key factor influencing the effectiveness of multiple treatments, and lower cost. It is logical to target the major CV risk factors, and therefore the current study opted for a combination of treatments targeting dyslipidaemia and blood pressure, together with antiplatelet therapy. Not only did the study show that FDC therapy improved adherence, but there was also small but significant incremental lowering of LDL-C and SBP compared with usual care. The limited magnitude of benefit for both risk factors is not unexpected given the extent of co-medication of the patient population at baseline.

The strengths of the study include large sample size, duration of follow-up, and completeness of data collection. Additionally, the study targeted a patient population at high CV risk rather than using a population-wide treatment approach. However, the authors also acknowledge a number of limitations that influence the generalisability of the study findings. Notably, subjects were recruited on the basis of their willingness to participate and attend clinic visits and were therefore probably more highly motivated than the general population. Additionally, the FDC group received their treatment in an open-label design and free of charge, whereas usual care was provided via routine care pathways and hence likely involved routine charges. Moreover, the study was not sufficiently powered to investigate effects on hard outcomes. Further study is also indicated to investigate whether a FDC strategy would provide net gain in an older population, given the potential risks of adverse events in patients with multiple co-morbidities.(3)

References

1. World Health Organization. Global Atlas on cardiovascular disease prevention and control. Available at http://whqlibdoc.who.int/publications/2011/9789241564373_eng.pdf.
2. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419-23.
3. Gaziano JM. Progress with the polypill? JAMA 2013;310:910-1.
4. Fruchart JC, Sacks F, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Diab Vasc Dis Res 2008;5:319-35.
5. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
6. International Atherosclerosis Society. An International Atherosclerosis Society Position Paper: Global Recommendations for the Management of Dyslipidemia. Available at http://www.athero.org/download/IASPP_Guidelines_ExSummary_2.pdf.

Key words

polypill; cardiovascular risk; adherence; fixed dose combination therapy