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These problems are especially serious in the communities of the Tiwi Islands, north of Darwin (population, about 1800) (Box 1). The incidence of ESRD among Tiwi people recently reached 2700 per million, and they have one of the highest CVD mortality rates in Australia.^2,4 In a community-wide screening program starting in the early 1990s, we found a high prevalence of cardiovascular risk factors, including type 2 diabetes and hypertension, and albuminuria (measured by the albumin/creatinine ratio (ACR) of a random urine specimen).⁵ Albuminuria correlated inversely with glomerular filtration rate (GFR), and its intensity predicted not only renal failure, but also cardiovascular deaths and all-cause natural deaths.^6-9

In the early 1990s, use of antihypertensive drugs was increasing gradually in the Tiwi communities, but systematic management of the huge burden of morbidity identified by the screening program was beyond the capacity of the existing health services. In November 1995, we therefore introduced a systematic treatment program to reduce blood pressure and to modify the expression and progression of renal and cardiovascular disease. We describe the results of this program to the end of 1998.

If antihypertensive drugs had been prescribed before entry into the study, they were discontinued or tapered when perindopril was started. Objectives were to achieve a minimum daily dose of 4 mg perindopril and to lower blood pressure, initially to < 130/85, but more recently to < 120/75.¹⁰ A stepped approach to achieve these blood pressures included increasing perindopril to 8 mg, with addition of long-acting calcium-channel blockers and/or diuretics if needed.

Participants were seen at least monthly while medications were introduced or changed, then at least every three months for the first year, and at least every six months thereafter. Each examination included a minimum of a brief history, medication review, and measurement of weight, blood pressure, urinary ACR and serum creatinine level and, in diabetics, evaluation of blood glucose control.

After a start-up period, the day-to-day program was largely conducted by local health workers and community project officers, who were supported by telephone contacts and regular visits by nurse coordinators from Darwin. Doctors, who reviewed eligibility assessments, supported or made treatment decisions and modified the protocols, were less intensively involved. The program has run in parallel with other clinic activities in Nguiu, Bathurst Island, but has been integrated into regular clinic activities at the Melville Island communities of Milikapiti and Pirlangimpi.

Treatment group: People eligible for ACEi therapy were those with:

• hypertension (blood pressure 140/90 mmHg);

• diabetes and ACR 3.4 g/mol (microalbuminuria threshold), regardless of blood pressure; or

• progressive overt albuminuria (ACR 34 g/mol on first testing and increasing over time), regardless of blood pressure or diabetes status.

All qualifying features needed to be confirmed on at least two occasions.

People with past adverse reactions and breastfeeding women were ineligible for ACEi therapy. Fertile women were advised about teratogenic risks and the options of contraception or discontinuation of ACEi medication early in unplanned pregnancy. People with serum creatinine levels over 250 µmol/L were considered ineligible for long-acting ACEi therapy in the first six months of the program, but were later enrolled when treatment proved safe and effective in people with mild and moderate renal insufficiency.

To some extent, enrolment was prioritised by disease severity. Thus, most people with overt albuminuria, uncontrolled blood pressure and renal insufficiency were enrolled in the first year of the program.

Control group: In the absence of a parallel control group, rates of renal failure and natural death in participants were compared with those of a historical control group from the pre-program period. This control group comprised adults whose results on a single screening examination between July 1992 and September 1995 met the eligibility criteria later used for the treatment program. Selection was blinded to their future course, which was followed to 30 October 1995.

Characteristics of people who enrolled are shown in Box 2: 42% had diabetes, almost two-thirds had hypertension, with a quarter already prescribed enalapril, and almost two-thirds had overt albuminuria.

Two-year clinical profiles for the 118 people are shown in Box 3. Treatment was associated with a swift and sustained fall in blood pressure, as well as stabilisation of ACR and GFR. Results are presented according to participants' clinical categories at baseline in Box 4. The fall in blood pressure was marked in people with hypertension at baseline and less marked but still apparent in those who had been normotensive, as well as in those previously prescribed an ACEi. Good blood pressure responses were seen in people both with and without diabetes, those with micro- and overt albuminuria and those with "normal" and raised levels of serum creatinine. Stabilisation of ACR and GFR was seen in all clinical categories. Indeed, serum creatinine level tended to fall and GFR to rise in all categories.

Baseline weight did not change (mean, 74 kg; SD, 16 kg), while mean serum potassium level rose non-significantly from 4.04 mmol/L (SD, 0.46 mmol/L) to 4.14 mmol/L (SD, 0.49 mmol/L). No one developed significant hyperkalaemia. There was no evidence that ACEi therapy accelerated progression to renal insufficiency.

Baseline characteristics of the control and intention-to-treat groups are compared in Box 2. The control group was younger at enrolment, had lower BMI, and included fewer people with diabetes or overt albuminuria. The control group was followed up for a total of 564 years (individual mean, 2.5 years; range, 1 month to 3.3 years) and the intention-to-treat group for 560 years (individual mean, 2.2 years; range, 2 weeks to 3.1 years).

Endpoints of the two groups are compared in Box 5. The treatment group as a whole had lower rates of dialysis, natural death and the combined endpoint (dialysis or death) than the control group, although the differences were not significant. However, rates of endpoints were strongly correlated with baseline ACR category. Indeed, renal failure necessitating dialysis was confined to people with ACR 100 g/mol at baseline, and in these people the treatment group had an estimated 57% lower dialysis rate than the control group. In contrast, rates of natural death and of the combined endpoint were lower in the treatment group than in the control group for all categories of baseline overt albuminuria. After adjustment for ACR category, the treatment group had an estimated 45% lower rate of natural death and an estimated 53% lower rate of the combined endpoint.

Box 6 shows estimates of the survival advantage in people with various baseline clinical profiles after adjustment for ACR category. Treatment benefit was strong in people with overt albuminuria, non-diabetic people and people with hypertension. It was less marked in diabetic or normotensive people.

Survival estimates for people with overt albuminuria at baseline are shown in Box 7. Although the intention-to-treat group showed attrition during the first year (representing ESRD and deaths of seriously ill people prioritised for early entry), a survival advantage over the control group was clear by two years of the treatment program.

The treatment program was also associated with a swift and dramatic decrease in rates of renal failure and natural death in the treated group compared with a historical control group, suggesting that the program prevented or at least delayed these outcomes. Further evidence for the existence of this estimated survival benefit was the decrease in community-wide rates of ESRD and natural death -- previously increasing -- after introduction of the program (Box 8). In contrast, ESRD continued to increase among non-Tiwi Aboriginal people in the Top End (Box 9), arguing against a chance background effect. Preliminary estimates of cost effectiveness of the program, based solely on avoidance or delay of dialysis, are already startling.^3,25

These results show that Aboriginal people are interested in health issues and receptive to health messages, and will take medications over the long term to protect against future health risk, with excellent response.

They also show that a systematic approach, with testing and treatment algorithms and clear goals, is superior to the previous approach of gradually improving medical management. While we cannot apportion relative benefit to individual elements of the treatment program, the observed fall in blood pressures alone would be expected to markedly reduce cardiovascular deaths and progression of renal disease,^10,11 compatible with the effects we found.

Our intention-to-treat analyses probably underestimate the therapeutic efficacy of treatment, as a third of the intention-to-treat group took the prescribed medications only occasionally or not at all. Use of the historical control group was also a potential source of bias. On the one hand, it may have also led to underestimates of treatment benefit because of the group's potentially better survival prospects, based on its younger mean age, milder disease and the probable inclusion of people with borderline blood pressure or ACR readings, as eligibility for the group was not confirmed by a second examination. On the other hand, the 123 controls who subsequently entered the treatment program might have had superior survival characteristics to the controls who did not enter the program, potentially inflating the apparent benefit of the program.

Another source of bias was the prioritisation of the sickest people for early enrolment in the treatment program, many of whom were failing previous management regimens. This predisposes to poor short term outcomes of the program and underestimates of its benefits. Analyses of program results at four and five years, when more people have passed through one to two years of treatment, will dilute the impact of these early events. Longer-term analyses will also be needed to evaluate any survival effect of treatment in people without overt albuminuria, and the extent to which treatment has delayed rather than prevented ESRD and death in people with overt albuminuria.

The program could still be improved. Blood pressure control should be better; at two-year follow-up, 31% of people had blood pressures 140/90, and 50% had blood pressures 120/75.¹⁰ Hypertension, and therefore eligibility for treatment even in the absence of albuminuria, should probably be redefined as blood pressures 130/80 in this high-risk population.¹⁰ Control of blood glucose and lipid levels needs to improve. Finally, we might reassess the notions of the maximally renal-protective dose of ACEi and/or add other renal-protective drugs, such as angiotensin II receptor blocking agents,^26,27 for poor responders.

Much of the success of this particular program derives from a strong sense of community ownership and control, a non-judgemental, non-authoritarian style, and respect for competing personal and community perspectives and priorities. Individuals appreciate personalisation of their health goals, and many are slowly adopting lifestyle changes.

This program is now being integrated into normal clinic activities at Nguiu. Its protocols have also been incorporated into standard care guidelines for Aboriginal adults in the Top End of the NT.²⁸ Extension of its principles to other Aboriginal communities with high burdens of disease nationwide is a matter of urgency.²⁹ Allocation of adequate resources is a challenge, but the clinical benefit and cost-effectiveness mandate the short- and intermediate-term investment.

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Reprints will not be available from the authors.
Correspondence: Dr W E Hoy, Menzies School of Health Research, PO Box 41096, Casuarina, NT, 0811.
wendyATmenzies.su.edu.au

©MJA 2000
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