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Included studies

We found 24 trials, with 28 active treatment arms, studying 58,040 patients, which met the inclusion criteria. Trials were only available to evaluate the effectiveness of four drug classes as first‐line drugs thiazides (19 trials in 39,713 patients), beta‐blockers (five trials in 19,313 patients), ACE inhibitors (three trials in 6002 patients), and calcium channel blockers (one trial in 4695 patients). Two trials evaluated thiazides as well as beta‐blockers versus placebo (MRC‐O 1992; MRC‐TMH 1985;); UKPDS 39 1998 evaluated beta‐blockers as well as ACE inhibitors versus placebo, and HYVET pilot 2003 evaluated thiazides as well as ACE inhibitors versus placebo, making 28 total comparisons from 24 trials. We did not identify any randomized controlled trials that compared first‐line alpha‐adrenergic blockers or angiotensin receptor blockers to placebo or untreated control group.

The average age of participants across all included trials was 62 years. Six trials were limited to patients over 60 years of age (EWPHE 1985; HYVET 2008; HYVET pilot 2003; Kuramoto 1981; MRC‐O 1992; SHEP 1991; SHEP‐P 1989; SYST‐EUR 1997). The age range in other trials was between 21 and 80 years. The mean age of patients from the four classes was: thiazide ‒ 61 years, beta‐blockers ‒ 56 years, ACE inhibitors ‒ 67 years, and calcium channel blockers ‒ 70 years.

Most participants were recruited from Western industrialized countries. Two trials did not report percentage of participants from different countries (HOPE HYP 2000; HYVET 2008). In 22 trials reporting recruitment of participants, 7750 (15.5%) were from USA, 32,907 (66%) from Europe; 3427 (6.9%) from Australia, and 91 (0.2%) from Japan. Females represented 45% of the population studied. Four trials included only men (OSLO 1986; VA‐I 1967; VA‐II 1970; VA‐NHLBI 1978) .

Fourteen trials did not report ethnicity (Barraclough 1973; Carter 1970; Dutch TIA 1993; EWPHE 1985; HOPE HYP 2000; HYVET 2008; HYVET pilot 2003; Kuramoto 1981; MRC‐TMH 1985; MRC‐O 1992; OSLO 1986; PATS 1996; SYST‐EUR 1997; TEST 1995). Ten trials reported ethnicity. African‐Americans comprised the following percentages in these trials: ATTMH 1980 (0%), HSCSG 1974 (80%), SHEP 1991 (13.8%), SHEP‐P 1989 (18%), UKPDS 39 1998 (7.6%), USPHSHCSG 1977 (28%), VA‐I 1967 ( 53.8%), VA‐II 1970 (42%), VA‐NHLBI 1978 (25%), and Wolff 1966 (89.6%).

The study population consisted of predominantly ambulatory patients recruited from the community, primary care centres, or hospital‐based clinics in 22 trials (57,982 patients, 99.7% of all patients included in this review). In the Kuramoto 1981 trial, 91 (0.2% of total) subjects were recruited from a home for the aged. Carter 1970 recruited 97 (0.3% of total) participants admitted to the hospital, who had survived an ischemic‐type major stroke.

In most trials, it was possible to determine whether the participants in the trials represented primary or secondary prevention. All trials excluded patients with angina and congestive heart failure, as these conditions would require use of antihypertensive drugs for reasons independent of their antihypertensive action. Some trials allowed patients with prior myocardial infarction or stroke, as long as they were not recent (e.g. within the previous three months). Thus, by determining the baseline prevalence of stroke and myocardial infarction, it was possible to calculate the percentage that represented secondary prevention. Three trials did not report prevalence of stroke or myocardial infarction, but it was likely low in these trials (Barraclough 1973; Kuramoto 1981; VA‐II 1970; 587 participants, (1.0% of total randomized participants). Six trials (11,157 patients) were primary prevention with less than 1% secondary prevention patients (ATTMH 1980 (0.4%); MRC‐O 1992 (0%); OSLO 1986 (0%); UKPDS 39 1998 (0%); USPHSHCSG 1977 (0%); and VA‐NHLBI 1978 (0%). Six trials (12,042 patients) were secondary prevention (Dutch TIA 1993 (100%); HOPE HYP 2000 (88%); HSCSG 1974 (96%); OSLO 1986 (0%); PATS 1996 (100%); and TEST 1995 (100%). Nine trials (34,041 patients) were mostly primary prevention patients (EWPHE 1985 (it was reported that the baseline prevalence of cardiovascular complications was 36% and these included conditions other than proven myocardial infarction and stroke); HYVET 2008 (12%); HYVET pilot 2003 (7%); MRC‐TMH 1985 (2.2%); SHEP 1991 (6.4%); SHEP‐P 1989 (5.5%); SYST‐EUR 1997 (reported as 30% patients with cardiovascular complications); VA‐I 1967 (7%);and Wolff 1966 (29%). The percentage of secondary patients in the 10 mostly primary prevention trials was 3212 (5.6%) of total randomized patients.

Thus, since 42,196 (72.7%) of total randomized people were primary prevention, the conclusions from this review are primarily relevant to the primary prevention setting.

Baseline prevalence of diabetes was reported in 8 trials as follows: HOPE HYP 2000 (38%); HYVET 2008 (7%); MRC‐O 1992 (0%); SHEP 1991 (10.1%); UKPDS 39 1998 (100%); USPHSHCSG 1977 (0%); VA‐I 1967 (9.1%); and Wolff 1966 (16.0%). Baseline prevalence of smoking was as follows: ATTMH 1980 (25.0%); EWPHE 1985 (16.0%); HYVET 2008 (6.5%); OSLO 1986 (41.7%); MRC‐TMH 1985 (28.5%); MRC‐O 1992 (36.0%); SHEP 1991 (13.0%); SHEP‐P 1989 (11.0%); SYST‐EUR 1997 (7.0%); UKPDS 39 1998 (22.3%); and USPHSHCSG 1977 (46.7%).

Recent trials defined stroke as the presence of neurological deficit lasting for more than 24 hours. It includes some patients with no disability. Older trials, like the HSCSG 1974, defined stroke as a neurological deficit lasting more than 24 hours, or a marked increase in transient ischemic attacks (twice the weekly pre‐randomization level of occurrence, more than four per week, or deterioration of more than eight points in neurological score). VA‐NHLBI 1978 defined stroke as typical weakness or paralysis. In some trials, stroke was not defined. In our opinion, lumping all strokes, including reversible ischemic neurological deficit (RIND), into one outcome is not optimal. More clinically relevant interpretations could be made if strokes were subdivided into three groups: strokes with no disability, strokes with mild disability, and strokes with severe disability. Myocardial infarction and sudden death were defined consistently across most trials. Myocardial infarction was defined as typical chest pain with ECG changes or increased cardiac enzymes; sudden death was defined as death within 24 hours of first evidence of acute cardiovascular disease, or unrelated to other known pre‐existing diseases.

Five trials restricted recruitment to persons with systolic hypertension; defined as systolic pressure 160 to 219 mmHg, and diastolic pressure less than 90 mmHg (SHEP 1991; SHEP‐P 1989), diastolic pressure less than 95 mmHg (SYST‐EUR 1997), or systolic pressure higher than 140 mmHg (TEST 1995), or higher than 160 mmHg (HYVET 2008). Six trials based entry on diastolic hypertension (Barraclough 1973; USPHSHCSG 1977; VA‐I 1967; VA‐II 1970; VA‐NHLBI 1978; Wolff 1966); and 10 trials based entry on either systolic or diastolic hypertension (ATTMH 1980; Carter 1970; EWPHE 1985; HSCSG 1974; HYVET pilot 2003; Kuramoto 1981; MRC‐TMH 1985; MRC‐O 1992; OSLO 1986; UKPDS 39 1998). HOPE HYP 2000 represented the subgroup of the HOPE trial that had a baseline blood pressure higher than 140 mmHg systolic, or higher than 90 mmHg diastolic. Two trials were included because more than 70% of patients at entry had a systolic BP higher than 140 mmHg (Dutch TIA 1993; PATS 1996).

Weighted mean baseline blood pressure for all the trials was 168/94 mmHg. When this was broken down into those that used systolic blood pressure as entry criteria, it was 173/84 mmHg; for those using diastolic pressure as entry criteria, it was 162/106 mmHg; and for those using both systolic and diastolic pressure as entry criteria, it was 167/97 mmHg. Two trials did not report baseline systolic pressure levels (Barraclough 1973;VA‐NHLBI 1978), and one trial did not report baseline diastolic pressure levels (VA‐NHLBI 1978).

For complete description of the blood pressure inclusion criteria for each study, see 'Participants' in the 'Characteristics of included studies' table.

A stepped approach to antihypertensive drug administration was used in 18 of the 24 trials. The exceptions were Dutch TIA 1993; HOPE HYP 2000; HSCSG 1974; PATS 1996; TEST 1995; and USPHSHCSG 1977, which used a standard dose of drug in the intervention arm. In 19 of the trials, a thiazide was the first‐line therapy in one of the arms of the trial. Because of a relatively large amount of data for thiazides, we were able to divide these 19 trials into those in which the thiazide starting dose was defined as low (8/19 trials, 874 patients) or high (11/19 trials, 19,839 patients), as explained in the methods. Three of the trials did not specify the thiazide dose, but were included in the high‐dose group because prescribing high doses of thiazides was common when those trials were conducted (Barraclough 1973; Carter 1970; OSLO 1986). The weighted mean dose of thiazide, in hydrochlorothiazide equivalents, was 90 mg for the high‐dose trials and 24 mg for the low‐dose trials. In five trials, a beta‐blocker was used as first‐line therapy in one of the arms of the trial (Dutch TIA 1993; MRC‐O 1992; MRC‐TMH 1985; TEST 1995; UKPDS 39 1998). Three trials used an angiotensin converting enzyme inhibitor, (HOPE HYP 2000; HYVET pilot 2003; UKPDS 39 1998). One trial used the calcium channel blocker nitrendipine (SYST‐EUR 1997). Second‐ and third‐line drugs included beta‐blockers, centrally‐acting drugs, peripherally‐acting anti‐adrenergic agents, vasodilators, thiazides, ACE inhibitors, alpha blockers, calcium channel blockers, and loop diuretics. See 'Interventions' in the 'Characteristics of included studies' table for a complete description of each study's drug treatment protocol.

Mean duration of follow‐up ranged from 1.1 years for the HYVET pilot 2003 trial to 10 years for the USPHSHCSG 1977 trial. The weighted average follow‐up was 4.1 years for the thiazide trials, 5.3 years for the beta‐blocker trials, 4.9 years for the ACE Inhibitor trials, and 2.5 years for the one calcium‐channel blocker trial.

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First‐line low‐dose thiazide compared to placebo for hypertension