Possibilities of multifactorial cardiovascular disease prevention in patients aged 75 and older: a randomized controlled trial

Drugs and Evidence Based Medicine in the Elderly (DEBATE) Study

Timo E Strandberg*, Kaisu Pitkala, Saila Berglind, Markku S Nieminen and Reijo S Tilvis

Department of Medicine, Geriatric Clinic and Division of Cardiology, University of Helsinki, Helsinki, Finland

* Correspondence to: Timo E Strandberg, MD, Department of Medicine, Geriatric Clinic, University of Helsinki, PO Box 340, FIN-00029 HUS, Finland. Tel: +358-9-471 72233; fax: +358-9-471 74013
E-mail address: timo.strandberg{at}hus.fi

Received 14 October 2002; revised 1 April 2003; accepted 3 April 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims The effectiveness of multifactorial cardiovascular disease prevention in patients aged 75 years or older is uncertain, because these patients have often been excluded from trials. The aim of this pre-planned, first-year analysis of the Drugs and Evidence-Based Medicine in the Elderly (DEBATE) Study was to determine the feasibility of prevention efforts in elderly cardiovascular patients.

Methods and results For DEBATE, home-dwelling individuals aged 75 years and over with cardiovascular diseases (n=400, mean age 80 years, 65% women) were recruited from the community. These high-risk participants were randomly assigned to the intervention group (n=199) where both lifestyle modification and pharmacological cardiovascular treatments are individualized by a geriatrician according to current European guidelines. The control group (n=201) receives the usual care. Interim analysis of the study groups at one year shows that intervention has succeeded in increasing the use of statins, aspirin, beta-blockers, and ACE inhibitors, and decreasing serum cholesterol (p<0.0001), LDL-cholesterol (p<0.0001), and hsCRP (p=0.04). Body mass index, blood pressure, and blood glucose were similar at one year in both groups. No safety problems or adverse effects on health-related quality of life were observed and compliance was good.

Conclusion It is possible and safe to institute evidence-based cardiovascular treatments in the 75+ cardiovascular patients in a real life setting, but only serum cholesterol and hsCRP are significantly decreased.

Key Words: Cardiovascular prevention • Elderly • Drugs • Multifactorial


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
An American Heart Association (AHA) Scientific Statement has recently updated the potential benefits of secondary prevention in the elderly1and urged for greater use of preventive therapies. However, there are still many uncertainties of the overall effectiveness of cardiovascular disease (CVD) prevention concerning both lifestyle modification and medical therapies in individuals aged 75 years and above, because oldest patients have usually been excluded from trials. For example, enrollment of patients aged 75 years or older in randomized trials of acute cardiac syndromes has been well below their representation among all patients with myocardial infarction.2The Drugs and Evidence Based Medicine in the Elderly (DEBATE) Study3was designed to assess the effect of multifactorialcardiovascular prevention in 75+ patients in a real-life setting. It differs from most previous studies4–6in that it is geriatrician managed, lasts 3 years, and uses both lifestyle and drug treatments in order to follow the existing guidelines. We report here the results of a pre-planned feasibility analysis3on the effects of the multifactorial intervention during the first year.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
The trial design including the randomization procedure and the flow chart of the DEBATE study have been published in detail previously.3Briefly, in a population-based setting, we have recruited 400 home-dwelling patients (75 to 90 years) into a ‘real life’ multifactorial, controlled secondary prevention trial. Pre-study mailed questionnaires were sent between November 1998 and March 1999 to a random sample of 75 to 95-year-old individuals (n=4821) living in Helsinki, Finland. The questionnaire included items on demographic characteristics, health, diseases, symptoms according to the NYHA class, and current drug treatment. All home-dwelling patients having an atherosclerotic disease (prior myocardial infarction, coronary artery disease, previous stroke or transient ischaemic attack, peripheral artery disease) and willing to participate were considered eligible, and were contacted by telephone by the study nurse. A second questionnaire was sent to possible participants, and they were invited to the clinic visit. The sample included more women than men because of the population-based retrieval. During the first visit, the atherosclerotic disease was confirmed, the patients signed an informed consent, whereafter they were randomized to the intervention (n=199) and control groups (n=201) of the multifactorial prevention study. The research protocol of the DEBATE study has been approved by the Ethics Committee of the Department of Medicine, University of Helsinki. The study follows the PROBE (prospective, randomized, open-blinded end-points) design. No specific exclusion criteria were set because of the real-life nature of the study.

All participants have CVD, mostly coronary heart disease (82%). In the intervention group (n=199), treatments are tailored according to current European guidelines7by a geriatrician-internist with consultations as appropriate. The procedures include oral and written (Finnish Heart Association guidelines, consistent with European guidelines) dietary advice, instructions to exercise three times a week for 1h with an exercise diary, and drug treatments according to current European guidelines. Structurized dietary advice concentrates on the type and amount of dietary fat, salt intake, increased use of fruit and vegetables and adjustment of total calories as needed. Smokers have been given advice on smoking cessation. The treatments of the intervention group are individualized and besides the yearly control visits, the intervening clinic visits are tailored as needed. The team also includes a physiotherapist to enhance exercise and deal with problems individually. Furthermore, participants with special problems can be sent to institutionalized rehabilitation. The control group (n=201) receives the usual care by primary care physicians, and only visits the study nurse (not the study geriatrician) yearly. The DEBATE study has been approved by the local ethics committee. Informed consent was obtained from all patients before study procedures.

At the 1-year evaluation all participants (intervention and control) visited the study nurse and baseline clinical evaluation and laboratory examinations were repeated.3Health-related quality of life was assessed with a validated 15D instrument.8Type and amount of exercise was assessed with questionnaires. High sensitivity C-reactive protein (hsCRP) is measured routinely as of 2001, and therefore baseline hsCRP were analysed from frozen (–20°C) serum samples. All laboratory measurements were performed in the centrallaboratory of the Helsinki University CentralHospital.

Comparisons were performed on an intention-to-treat basis with the NCSS statistical program (www.ncss.com). Analysis of covariance was used to compare continuous variables at one year with baseline value as covariate. Pvalues <0.05 were considered statistically significant.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Baseline characteristics of the randomized study groups are shown in Table 1. The groups were well balanced regarding CVD and risk factors. Only statistically significant difference was observed in serum LDL-cholesterol which was significantly lower in the intervention group than the control group. This was due to significantly lower LDL-cholesterol in the men of the intervention group (2.99mmol/l, SD 0.79 vs 3.25mmol/l SD0.68, in the control group). LDL-cholesterol values among women were higher (average 3.35 to 3.49mmol/l) than men in both groups but not significantly different between groups Serum HDL-cholesterol was significantly lower in men (average values 1.32 to 1.37mmol/l in the two groups) than in women (average 1.57mmol/l in both groups), but the values were not significantly different between the intervention and control groups. Treatments and risk factors at one year were available from 92% and 90% of the intervention and control groups, respectively. Ten individuals had died in both groups during the first year.


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Table 1 Baseline characteristics of the DEBATE Study participantsa

 
In the intervention group, besides routine oral and written advice given to all participants, special, individualized advice by the geriatrician on diet and exercise were given to 25% and 38% of the patients, respectively. In addition, the physiotherapist made a home-visit to 35 participants to deal with special problems related to physical function.

In the intervention group, there has been aclear and significant increase in the use of several evidence-based medications (aspirin, beta-blockers, ACE-inhibitors, statins, Fig. 1). In addition, the use of diuretics was significantly more prevalent in the intervention group than the control group at one year (39.9% vs 23.9%, p=0.0009). No significant differences were observed in the use of AII blockers (6.6% vs 5.6% in controls), calcium-channel blockers (28.4% vs 23.9% in controls), warfarin (11.5% vs 11.7% in controls), or anti-diabetic drugs (12.6% vs 10.6% in controls.



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Fig. 1 Percent use of evidence-based cardiovascular drug treatments in the study groups at baseline and at 1 year. *Indicates statistically significant (p=0.04 or less) difference vs control group.

 
Intervention affected significantly serum total and LDL-cholesterol (p<0.0001), whereas body mass index (BMI), waist circumference, and blood pressure were not statistically different (Table 2). Reported exercise, and calf and brachial circumferences were similar (data not shown). In contrast, blood glucose was slightly higher in the intervention group at 1 year (p=0.03), although change from baseline was not significantly different. Using analysis of covariance to take baseline values into account, serum hsCRP was significantly lower in the intervention group (p=0.04). Baseline smoking was rare (6%), but two individuals in the intervention (vs none in the control group) had quit smoking during the first year. Serum creatinine was slightly, but significantly higher in the intervention group (p=0.04). Patients of the intervention group reached total serum cholesterol (<5.0mmol/l) and LDL cholesterol (<3.0mmol/l) goals significantly more often, whereas the prevalence of obesity (BMI <30kg/m2), hypertension (SBP <140mmHg) andhyperglycaemia (blood glucose <5.5mmol/l) was not significantly different.


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Table 2 One-year clinical and laboratory characteristics and their changes from baseline in the intervention and control groups of the DEBATE Study

 
All the health related quality of life dimensions of the 15D were similar without statistically significant differences in the two groups at 1 year (data not shown). No specific and serious adverse effects related to the study procedures in the intervention group have been observed during the first year.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
The DEBATE study deals with the oldest cardiovascular patients, who have often been excluded from randomized controlled trials. Our interim results add the following important information to the existing knowledge: First, it is possible—in a ‘real life’ setting—to convert the CVD treatments of even 75+ high-risk patients more evidence-based, and the present CVD drug treatments in the intervention group now resemble the treatments in younger coronary patients.9Second, it is also possible to affect some of the risk factors favourably. Importantly, these procedures have not had adverse effects on the quality of life in these oldest patients. However, careful economic analyses are needed to show whether these efforts are also cost-effective and these analyses will be performed when the clinical end-point results are available.

Its is entirely possible that even the existing treatments and current risk factor levels of the control group are sufficient, and the ‘optimization’ of CVD treatments in this age group offers no more extra value. This is an important question, but to answer it we need to complete our study. For reliable answers we also need to show that risk factors are improved and that the treatments are safe. Evidence-based treatment of CVD leads to a substantial increase of drug use with a greater likelihood of drug interactions.10Our experience is reassuring: despite medications no clinically significant differences in the safety variables were observed and quality of life was not adversely affected. On the other hand, awareness of adverse renal effects and hyperkalaemia as well as the reimbursement policy in Finland are the main reasons why the prevalence of ACE-inhibitors in our study is not up to the level of current evidence.11Weobserved a slight increase in mean serum creatinine levels in the intervention group, possibly due to the increased use of ACE-inhibitors, but this is not considered clinically important. In fact, a recent study of ACE-inhibitor treatment in frail elderly showed that even patients with perceived contraindications (hypotension, hyperkalaemia, renal insufficiency) had survival benefit from these drugs.12

Lifestyle changes are important in the prevention of CVD, and weight reduction and exercise prevent type 2 diabetes in midlife.13,14Recent analyses in Europe have shown that mortality has declined also in the population aged 75–84 years,15and a sizable part of this development is probably due to lifestyle changes at the population level. In the intervention group, all participants were routinely given structurized dietary and exercise counselling according to national guidelines. This is also the ‘real-life’ situation of advice. In addition, special advice on diet and exercise was given to substantial number of participants. According to our experience of routine health care in Helsinki, the efforts on lifestyle changes have clearly exceeded those in usual health care of the elderly. However, this extra effort was not reflected in the clinical measures of body weight and composition. This was somewhat expected in a geriatrician-driven study, because malnutrition is a real concern in the elderly,16and doctors must be prudent in their advice. On the other hand, there are very few studies of possibilities of weight reduction and its benefits specifically in the oldest age groups.1The TONE trial17showed benefits of reduced sodium intake and weight loss in hypertensive patients aged 60 to 80 years at baseline. However, 78% of the TONE population was less than 70 years of age, and results in older participants are not reported. In the DEBATE study, because of its multifactorial nature, it is difficult to separate pharmacological and non-pharmacological effects, but we plan to analyse serum fatty acid composition of the participants at 1 year in order to get objective insight of the effects of dietary modification.

More unexpected was that we could not demonstrate a significant effect on blood pressure, despite the lifestyle advice and a significant increase in the use of all main anti-hypertensives. It is possible that the sample is too small to demonstrate a statistically significant effect, the mean systolic pressure was nevertheless lower in the intervention group (146mmHg) than the control group (150mmHg). In a meta-analysis of recent hypertension trials, only a 2–3mmHg mean net difference was observed.18In the elderly, over-zealous pursuit of treatment goals is probably best avoided, but the safety and efficacy of anti-hypertensive treatment in the oldest-old must be settled in ongoing explanatory trials.19,20

The most clear-cut intervention effect achieved was the lowering of total and LDL cholesterol levels. This is probably due to the increase of statin use. Because statins reduce hsCRP,21they may also explain the significant hsCRP decrease. Evidence from unifactorial studies is accumulating and suggest that statin treatment is beneficial in high-risk patients up to 82 years.22,23A non-randomized study has suggested that statin use is associated with a smaller risk of recurrent myocardial infarction without upper age limit.24Our data suggest that it is feasible and safe to institute statin therapy in a large number of community-dwelling 75+ individuals.

In conclusion, our feasibility analysis indicates that it is possible and safe to improve preventive efforts also in the CVD patients aged 75 years and above in real life. Because of the central role of cholesterol and inflammation in the pathogenesis of vascular diseases, these results are promising for favourable outcomes also in the clinical end-points of the DEBATE study.


    Acknowledgments
 
The Academy of Finland (Grant 48613), the Lions Organization (Punainen Sulka-Red Feather the Ragnar Ekberg Foundation, and the Helsinki University Central Hospital are gratefully acknowledged for financial support.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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