Arterial hypertension is the most frequent cardiovascular disorder, with a prevalence of approximately 20%. Early detection and treatment of hypertension is particularly important when it is considered that it is one of the major risk factors for cerebrovascular and cardiovascular morbidity and mortality (1). The fact that only 30-40% of patients treated reached normal blood pressure and that a considerable number of hypertensive patients are not treated at all emphasizes the call for increased efforts in the early detection and treatment of hypertensive patients. Alongside diuretics, calcium-channel blockers and adrenergic α-blockers, angiotensin-converting enzyme (ACE) inhibitors have been first-line agents in the treatment of arterial hypertension for many years (2). High efficacy and good tolerability combined with a range of positive accompanying effects are the essential characteristics of substances belonging to this drug group. Spirapril, a new ACE inhibitor, has been widely used in Germany in a clinical setting since January 1997. According to available clinical trials, it is a substance that is highly effective and well tolerated. It has a simple dosage and a 24 h effect with once-daily administration as well as a dual excretion mechanism (3-8). Since its introduction, more than 30 000 patients have been treated with this preparation. A multicentre post-marketing surveillance study conducted by general practitioners had the aim of formulating statements on the efficacy and tolerability of this preparation with single daily use in a random sample of 5000 patients.
PATIENTS AND METHODS
This post-marketing surveillance study had a prospective, multicentre design and included patients with essential hypertension. The data of 5000 patients treated with spirapril from January 1997 until the end of May 1997 were evaluated. Demographic data and tolerability were evaluated for all patients. Efficacy, however, was only evaluated for 4685 patients (93.7%) with a documented diagnosis of essential hypertension. Included in the trial were patients with varying degrees of hypertension from borderline hypertension to moderate and severe forms of hypertension. According to the non-interventional character of a post-marketing surveillance study, the doctor was not given any diagnostic or treatment criteria.
The following data were recorded at the baseline investigation: demographic patient data; indication for spirapril treatment; cardiovascular risk factors and concomitant diseases; treatment to date; concomitant treatment during the post-marketing surveillance study; blood pressure and heart rate at rest in the sitting position; and subjective well-being.
Of the 5000 patients, 25.6% had not received any antihypertensive treatment before the start of the post-marketing surveillance study and 74.4% had already been treated with antihypertensive drugs; 65.9% of the patients who had been treated previously received single drug treatment, 25.6% a combination of two preparations, 7% a combination of three preparations, and 1.5% a combination of four or five preparations. Diuretics and ACE inhibitors were used approximately to the same extent (21.2% and 22.3%, respectively), β-blockers and calcium-channel blockers were used only slightly more often (26.8% and 30.2%, respectively); 4259 patients (85.2%) were treated with a single daily dose of 6 mg spirapril (Quadropril®) for the entire observational period of 12 weeks; 1348 patients were treated only with spirapril during the observational period; 2993 patients received combination treatment.
The study lasted for 12 weeks and included four documentation dates, one at the start of treatment and three examinations (at 4, 8 and 12 week) during treatment.
There were approximately the same number of women (46.7%) and men (53.0%) and the average age was 60.0 years; 77% of the patients had at least one further disease or a cardiovascular risk factor. The most common concomitant diseases were metabolic disorders (lipid disorder, diabetes mellitus, hyperuricaemia).
Blood pressure and heart rate in the sitting position, dosage, subjective well-being using a four-stage scale and laboratory values taken during treatment were documented at all examination dates. All adverse drug reactions which occurred were also documented. At the end of the observational period, doctors evaluated the efficacy and tolerability of spirapril using a four-stage scale. The reasons for any premature withdrawals from the study were also documented.
The data collected by the doctors were transferred to standardized record sheets and evaluated using the SPSS 6.1 for Windows statistical program after data entry and storage in a computer database.
Blood pressure on spirapril treatment
In the random sample of patients with essential hypertension that may be regarded as representative, spirapril induced a marked reduction in systolic and diastolic blood pressure. During the 12-week treatment period, blood pressure fell on average from 175.5/99.8 mm Hg at baseline to 146.9/85.1 mm Hg at the end of the study. Thus, spirapril caused a mean reduction in systolic blood pressure of 28.6 mm Hg and a mean reduction in diastolic blood pressure of 14.7 mm Hg. The responder rates were 89.4% for systolic blood pressure (n = 4341) and 85.4% for diastolic blood pressure (n = 4337).
Differentiated evaluation of the antihypertensive effects in single drug treatment using spirapril as compared to use in combination treatment showed that blood pressure was reduced to approximately the same extent with comparable baseline values (Fig. 1). The extent of the antihypertensive efficacy of spirapril was also markedly dependent on baseline blood pressure and thus on the severity of hypertension. This was proved by the differentiated evaluation of antihypertensive efficacy in relation to the severity of hypertension according to the World Health Organization (WHO) classification for systolic and diastolic blood pressure. It showed that the antihypertensive effect is clearly dependent on baseline blood pressure (Figs 2 and 3); the higher the blood pressure, the more marked the antihypertensive effect. Thus, spirapril was confirmed to be suitable for treatment of all degrees of severity of hypertension. In addition, the maximum antihypertensive effect achieved did not occur immediately, a phenomenon that could cause adverse drug reactions. Rather, it developed gradually over the 12 weeks of treatment (Fig. 4). The lack of efficacy of spirapril in patients with normal blood pressure is clinically significant. Thus, there is a small risk of adverse hypotensive effects in patients with normal blood pressure. In addition to a significant (p < 0.001) shifting of systolic and diastolic blood pressure values to lower values, classification of blood pressure values on the basis of the WHO classification (9) at the start and at the end of the post-marketing surveillance study also showed a particularly marked improvement in diastolic blood pressure (Table 1). The improvement in blood pressure values was two or more classes more marked for diastolic than for systolic blood pressure (Fig. 5). The normalization rate achieved was accordingly higher.
During the 12 weeks of treatment, heart rate decreased from an average of 78.8 beats/min to 74.8 beats/min. A reduction in heart rate was observed in 60.9% of patients, which is an effect probably caused indirectly by the reduction in blood pressure and relieving of the heart. No change in heart rate was observed in 16.6% of patients and an increase in heart rate was seen in 22.5% of patients during the course of treatment.
At the four documentation examinations, the patients were asked to evaluate their subjective well-being as 'very good', 'good', 'satisfactory' or 'unsatisfactory'. Evaluation of these data showed a clear improvement in well-being during the 12 weeks of treatment. This was shown by the increase in the number of patients assessing their well-being as 'very good' and 'good' and the decrease in the number of patients assessing their well-being as 'satisfactory' or 'unsatisfactory'. Before the start of treatment, 547 patients assessed their well-being as 'very good' and 1542 patients as 'good'. After 12 weeks of treatment, these figures increased to 1739 and 2328 patients, respectively. The 'satisfactory' assessment decreased from 1765 to 192 patients and the 'unsatisfactory' assessment decreased from 749 to 15 patients.
Adverse drug reactions
147 patients experienced at least one adverse drug reaction, which is equivalent to an incidence of side effects of 2.9%. These adverse reactions were exclusively non-severe, known and typical side effects of ACE inhibitors. Table 2 shows side effects with an incidence of >0.50%. Coughing, the most common side effect, occurred in only 44 patients (0.88%). Headache, dizziness and flush, which are further typical side effects of ACE inhibitors, had an incidence of <0.30%, which supports the known low incidence of side effects for spirapril in the therapeutic dosage range seen in controlled clinical trials.
Treatment was discontinued prematurely in 84 patients (1.7%). The reasons for this were adverse drug reactions in 37 of these patients, insufficient efficacy in 27 patients and non-compliance in eight patients. Treatment was discontinued in seven patients who had changed their doctor and treatment and in five patients without comments.
Subjective evaluation of spirapril treatment
The good antihypertensive efficacy of spirapril was also reflected in the subjective evaluation of efficacy by the attending doctors. They assessed efficacy as very good or good for 91.4% of patients. The efficacy was assessed as satisfactory in only 5.6% of patients and poor in 2.1% of patients.
The tolerability of spirapril was also predominantly (95.3%) assessed as being very good or good. Tolerability was assessed as being satisfactory in only 1.3% of patients and poor in 0.5%. No data were available for this parameter for 2.9% of patients. Finally, the doctors were to indicate whether treatment with spirapril would be continued after the post-marketing surveillance study. In this respect, the doctors stated that they intended to continue spirapril treatment in 4647 patients (92.9%). They stated that they would not continue spirapril treatment in 182 patients (3.6%) and no data were given for 171 patients (3.4%).
Hypertension over a long period of time is associated with an elevated cardiovascular risk and a decrease in statistical life expectancy (1). Early detection and treatment of arterial hypertension is the best method for primary prevention of more severe cardiovascular and cerebrovascular diseases such as stroke, myocardial infarction, heart failure, nephropathy and other complications of hypertension. However, this requires a continuous decrease in blood pressure into the normal range, current recommendations setting the goal for systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg. The more demanding (lower) target blood pressure values as compared to those in earlier years are a result of current evaluation of epidemiological studies available on the relationship between blood pressure and cardiovascular morbidity and mortality (1). This is also seen in the current recommendations of the German Hypertension League dated November 1997 (2) and in the report of the American Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (10). These documents emphasize recommendations on individualized, differentiated treatment whose efforts towards optimum reduction in blood pressure should be oriented on concomitant diseases and accompanying risk factors. Striking is the definition 'high normal blood pressure', used for the first time in the JNC report. This considers the fact that there is a fluid transition between normal and elevated blood pressure and that some patients with normal blood pressure should be classified as requiring treatment when their risk situation is considered. This applies to diabetic patients for example with incipient and, in particular, with advanced nephropathy in whom blood pressure if possible should be reduced to target values of around 120/80 mm Hg. In the sixth JNC report (10), American hypertension researchers recommend the use of ACE inhibitors, calcium-channel blockers, and α1-blockers as first-line agents in addition to diuretics and β-blockers. This is in accordance with the longer existing German recommendations.
ACE inhibitors have been used for a long time now in the treatment of hypertension. They block ACE, which converts angiotensin I into angiotensin II and is biologically very active. This leads to less angiotensin II being formed, which in turn causes a reduction in blood pressure and further positive effects. For example, due to their profile of action, ACE inhibitors such as spirapril are particularly beneficial for hypertensive patients with concomitant heart failure, those who have had a myocardial infarction or hypertensive patients with diabetes mellitus. Other essential advantages are effective regression of left ventricular hypertrophy and a nephroprotective effect (11-14).
Post-marketing surveillance studies complement controlled clinical trials by enabling clinical experience to be gathered on efficacy and tolerability (15,16). Experience gained under daily practice conditions, without the exactly determined conditions with strict inclusion and exclusion criteria as in controlled clinical trials, enables statements to be made about the efficacy and tolerability of a drug, mostly on the basis of larger sample sizes.
This post-marketing surveillance study had the aim of gathering experience on the efficacy and tolerability of spirapril, an ACE inhibitor, in the treatment of hypertension in broad clinical use. In accordance with the findings of controlled clinical trials, the results confirm the effective reduction of systolic and diastolic blood pressure with single daily administration of 6 mg spirapril. The larger sample size in the post-marketing surveillance study enabled differentiated evaluation of the antihypertensive efficacy in relation to the severity of the hypertension, and evaluation of the antihypertensive efficacy in single drug treatment as compared to use in combination treatment.
The findings confirm those from controlled clinical trials (3-7) on the effective reduction of systolic and diastolic blood pressure with single daily administration of spirapril, 85.2% of patients being treated with a single daily dose of 6 mg spirapril during the entire observation period. The result of 12 weeks of treatment was a mean reduction in systolic blood pressure of 28.6 mm Hg and in diastolic blood pressure of 14.7 mm Hg. This is a very marked effect which is reflected in very good responder rates of 89.4% for systolic blood pressure and 85.4% for diastolic blood pressure.
The findings showed practically equal efficacy of spirapril in single drug treatment and in use in combination treatment. It was also shown that the antihypertensive effect, both for systolic and diastolic blood pressure, was markedly dependent on baseline blood pressure. The higher the blood pressure, the greater the antihypertensive effect during the 12 weeks of treatment. In addition, classification of the blood pressure effects according to WHO recommendations on grading of the severity of hypertension showed that spirapril caused a particularly marked reduction in diastolic blood pressure. Thus spirapril was proved to be a very effective substance which can be used in all degrees of severity of hypertension and whose antihypertensive effect is particularly marked in the case of very high blood pressure, without an adverse reduction in blood pressure occurring in milder forms of hypertension. Accordingly, the doctors evaluated the efficacy of spirapril as very good or good in 91.4% of patients. The tolerability of spirapril was also evaluated as very good or good in the majority of patients (95.3%) which is also emphasized by the low number of adverse drug reactions. The incidence of side effects was only 2.9%; usual, typical side effects of ACE inhibitors had only a very low incidence. This also applies to dry cough, which occurred in only 0.88% of patients. Thus the broad use of spirapril confirms the results obtained in controlled clinical trials, i.e., that with therapeutic doses of spirapril, the incidence of side effects is in the placebo range and that only headache occurred more often than was the case for placebo.
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A Spirapril symposium held in Vienna, Austria, August 25, 1998
The symposium and the publication of this supplement were supported by an educational grant from ASTA Medica AG, Frankfurt am Main, Germany.