MICARDIS®

Efficacy

Primary hypertension

The antihypertensive effects of MICARDIS® have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20-160 mg; one of these examined the antihypertensive effects of telmisartan and hydrochlorothiazide in combination. The studies involved a total of 1,773 patients with mild to moderate hypertension (diastolic blood pressure of 95-114 mmHg), 1,031 of whom were treated with telmisartan. Following once daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.

Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with MICARDIS® tablets, blood pressure gradually returned to baseline values over a period of several days to one week. During long term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year. The antihypertensive effect of telmisartan is not influenced by patient age, gender, weight, or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors.

In a controlled study, the addition of telmisartan to hydrochlorothiazide produced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with telmisartan monotherapy. Hydrochlorothiazide also had an added blood pressure effect when added to telmisartan.

The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of telmisartan is maintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40-80 mg doses of telmisartan was 70-100% for both systolic and diastolic blood pressure. The incidence of symptomatic orthostasis after the first dose in all controlled trials was low (0.04%).

There were no changes in the heart rate of patients treated with telmisartan in controlled trials.

Cardiovascular Risk Reduction

Support for use to reduce the risk of cardiovascular events was obtained in a pair of studies. Both enrolled subjects age ≥55 years, at high cardiovascular risk as evidenced by coronary artery disease (75%), diabetes mellitus (27%) accompanied with end-organ damage (e.g., retinopathy, left ventricular hypertrophy, and, in ONTARGET only, macro- or microalbuminuria), stroke (16%), peripheral vascular disease (13%), or transient ischemic attack (4%). Patients without a history of intolerance to ACE inhibitors entered ONTARGET, and those with such a history, usually cough (90%), entered TRANSCEND, but patients with >1+ proteinuria on dipstick were excluded from TRANSCEND. For both ONTARGET and TRANSCEND trials, the primary 4-component composite endpoint was death from cardiovascular causes, myocardial infarction, stroke, and hospitalization for heart failure. The secondary 3-component composite endpoint was death from cardiovascular causes, myocardial infarction, and stroke.

ONTARGET was a randomized, active-controlled, multinational, double-blind study in 25,620 patients who were randomized to telmisartan 80 mg, ramipril 10 mg, or their combination. The population studied was 73% male, 74% Caucasian, 14% Asian, and 57% were 65 years of age or older. Baseline therapy included acetylsalicylic acid (76%), lipid lowering agents (64%), beta-blockers (57%), calcium channel blockers (34%), nitrates (29%) and diuretics (28%). The mean duration of follow up was about 4 years and 6 months. During the study, 22.0% (n=1,878) of telmisartan patients discontinued the active treatment, compared to 24.4% (n=2,095) of ramipril patients and 25.3% (n=2,152) of telmisartan/ramipril patients.

TRANSCEND randomized patients to telmisartan 80 mg (n=2,954) or placebo (n=2,972). The mean duration of follow up was 4 years and 8 months. The population studied was 57% male, 62% Caucasian, 21% Asian, and 60% were 65 years of age or older. Baseline therapy included acetylsalicylic acid (75%), lipid lowering agents (58%), beta-blockers (58%), calcium channel blockers (41%), nitrates (34%) and diuretics (33%). During the study, 17.7% (n=523) of telmisartan patients discontinued the active treatment, compared to 19.4% (n=576) of placebo patients.

The results for the TRANSCEND trial are summarized in Table 1, and the results for ONTARGET are summarized in Table 2, below: (Table 1,2)

Table 1. Incidence of the primary and secondary outcomes from TRANSCEND

	No. of events Telmisartan/placebo	Hazard ratio 95% CI	p-value
	Telmisartan (n=2,954) vs. placebo (n=2,972)
*Composite of CV death, myocardial infarction, stroke, or hospitalization for heart failure	465 (15.7%) / 504 (17.0%)	0.92 (0.81 – 1.05)	0.2129
*Composite of CV death, myocardial infarction, or stroke	384 (13.0%) / 440 (14.8%)	0.87 (0.76 – 1.00)	0.0483
Individual components of the primary composite endpoint	No. of events Telmisartan/placebo	Hazard ratio 95% CI	p-value
^†All non-fatal MI	114 (3.9%) / 145 (4.9%)	0.79 (0.62 – 1.01)	0.0574
^†All non-fatal strokes	112 (3.8%) / 136 (4.6%)	0.83 (0.64 – 1.06)	0.1365

Table 2. Incidence of the primary and secondary outcomes from ONTARGET

	No. of events telmisartan/ramipril	Hazard ratio 97.5% CI
	Telmisartan (n=8,542) vs. ramipril (n=8,576)
Composite of CV death, myocardial infarction, stroke, or hospitalization for heart failure	1,423 (16.7%) / 1412 (16.5%)	1.01 (0.93 – 1.10)
Composite of CV death, myocardial infarction, or stroke	1,190 (13.9%) / 1210 (14.1%)	0.99 (0.90 – 1.08)

Although the event rates in ONTARGET were similar on telmisartan and ramipril, the results did not unequivocally rule out that MICARDIS® may not preserve a meaningful fraction of the effect of ramipril in reducing cardiovascular events. However, the results of both ONTARGET and TRANSCEND do adequately support MICARDIS® being more effective than placebo would be in this setting, particularly for the end point of time to cardiovascular death, myocardial infarction, or stroke.

In ONTARGET, there was no evidence that combining ramipril and MICARDIS® reduced the risk of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure greater than ramipril alone; instead, patients who received the combination of ramipril and telmisartan in ONTARGET experienced an increased incidence of clinically important renal dysfunction (e.g., acute renal failure) compared to patients receiving MICARDIS® or ramipril alone.

Multiple sub-group analyses did not demonstrate any differences in the 4-component composite primary endpoint based on age, gender, or ethnicity for either ONTARGET or TRANSCEND trial.

Footnotes:

ACE, angiotensin converting enzyme; BP, blood pressure; CI, confidence interval; CV, cardiovascular; DBP, diastolic blood pressure; MI, myocardial infarction; SBP, systolic blood pressure
*The primary endpoint was defined as the time to first event. In case of multiple simultaneous events, all individual events were considered; the sum of patients with individual outcomes may exceed the number of patients with composite (primary or secondary) outcomes.
^†For individual components of the primary composite endpoints, all events, regardless whether or not they were the first event, were considered. Therefore, they are more than the first events considered for the primary or secondary composite endpoint.